TLR4

Summary

TLR4 (toll like receptor 4, HGNC:11850) is a protein-coding gene on chromosome 9q33.1, encoding Toll-like receptor 4 (O00206). Transmembrane receptor that functions as a pattern recognition receptor recognizing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) to induce innate immune responses via downstream signaling pathways.

The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. In silico studies have found a particularly strong binding of surface TLR4 with the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease-2019 (COVID-19). This receptor has also been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness, and with susceptibility to age-related macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 7099 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inflammatory bowel disease (Limited, GenCC)
• GWAS associations: 48 (top 2% of genes corpus-wide)
• Clinical variants (ClinVar): 124 total
• GTEx eGene: eQTL in 29 tissues, sQTL in 5 (q < 0.05)
• Phenotypes (HPO): 85
• Drug target: yes — 1 curated mechanism-of-action drug, 1 via a complex or family; 6 molecules with ChEMBL bioactivity
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.86 (unconstrained)
• MANE Select transcript: NM_138554
• Interaction hub: 5,887 STRING partners (top 1% of genes corpus-wide)
• Notable: 124 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11850
Approved symbol	TLR4
Name	toll like receptor 4
Location	9q33.1
Locus type	gene with protein product
Status	Approved
Aliases	hToll, CD284, TLR-4, ARMD10
Ensembl gene	ENSG00000136869
Ensembl biotype	protein_coding
OMIM	603030
Entrez	7099

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000355622

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 3: 1

ENST00000355622, ENST00000394487, ENST00000472304, ENST00000490685, ENST00001119368

RefSeq mRNA: 3 — MANE Select: NM_138554 NM_003266, NM_138554, NM_138557

CCDS: CCDS6818

Canonical transcript exons

ENST00000355622 — 3 exons

Exon	Start	End
ENSE00003979002	117704403	117704565
ENSE00003979003	117708563	117708729
ENSE00004782780	117712389	117724735

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 95.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.9753 / max 2316.9255, expressed in 1287 samples.

Highest expression (Bgee): monocyte, mononuclear cell, leukocyte, calcaneal tendon, blood.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TLR4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 29 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 34 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	1.2e-77	-0.28	9:117700861:A:G
Artery Aorta	eqtl	5.3e-14	-0.29	9:117679668:C:T
Heart Left Ventricle	eqtl	7.0e-14	-0.38	9:117678985:C:T
Esophagus Muscularis	eqtl	2.1e-10	+0.25	9:117702042:T:C
Artery Tibial	eqtl	8.5e-10	-0.19	9:117665121:A:G
Heart Atrial Appendage	eqtl	1.7e-08	-0.33	9:117679668:C:T
Nerve Tibial	eqtl	2.0e-07	-0.27	9:117678985:C:T
Brain Nucleus accumbens basal ganglia	eqtl	8.9e-07	-0.75	9:117737869:A:G
Brain Cerebellum	sqtl	4.8e-06	+0.84	9:117780345:A:AT
Brain Cerebellum	eqtl	1.6e-04	+0.31	9:117720825:A:G
Brain Spinal cord cervical c-1	eqtl	2.0e-04	-0.26	9:117661425:G:A
Muscle Skeletal	eqtl	2.3e-04	-0.16	9:117679668:C:T
Cells Cultured fibroblasts	eqtl	1.2e-03	-0.14	9:117688520:A:G
Brain Caudate basal ganglia	eqtl	1.3e-03	-0.59	9:117737869:A:G
Brain Hippocampus	eqtl	1.8e-03	-0.21	9:117651461:C:G
Brain Putamen basal ganglia	eqtl	2.1e-03	-0.63	9:117728460:A:G
Brain Frontal Cortex BA9	eqtl	2.6e-03	-0.16	9:117676199:T:C
Cells Cultured fibroblasts	sqtl	2.7e-03	+0.60	9:117710902:C:T
Spleen	eqtl	8.2e-03	-0.17	9:117700437:A:G
Lung	sqtl	9.6e-03	+0.69	9:117708220:A:C

FANTOM5 promoters

showing 10 of 11 alternative TSS:

Promoter ID	TPM avg	Samples expressed
98301	22.2542	1059
98297	4.3785	850
98298	3.4126	675
98293	2.9915	761
98300	1.3079	426
98294	1.2630	504
98299	1.0894	375
98296	0.6445	222
98295	0.4086	160
98303	0.1200	61

Top tissues by expression

showing 100 of 273 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	95.59	gold quality
mononuclear cell	CL:0000842	95.29	gold quality
leukocyte	CL:0000738	95.00	gold quality
calcaneal tendon	UBERON:0003701	94.53	gold quality
blood	UBERON:0000178	92.25	gold quality
tendon	UBERON:0000043	87.04	gold quality
bone marrow	UBERON:0002371	85.38	gold quality
trabecular bone tissue	UBERON:0002483	84.57	gold quality
spleen	UBERON:0002106	84.31	gold quality
granulocyte	CL:0000094	84.22	gold quality
omental fat pad	UBERON:0010414	84.19	gold quality
peritoneum	UBERON:0002358	84.12	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.73	gold quality
right lung	UBERON:0002167	83.35	gold quality
gall bladder	UBERON:0002110	82.68	gold quality
bone marrow cell	CL:0002092	82.45	gold quality
subcutaneous adipose tissue	UBERON:0002190	82.19	gold quality
vermiform appendix	UBERON:0001154	81.90	gold quality
adipose tissue	UBERON:0001013	81.30	gold quality
connective tissue	UBERON:0002384	81.22	gold quality
descending thoracic aorta	UBERON:0002345	80.57	gold quality
layer of synovial tissue	UBERON:0007616	80.23	gold quality
adrenal tissue	UBERON:0018303	80.23	gold quality
upper lobe of left lung	UBERON:0008952	80.18	gold quality
upper lobe of lung	UBERON:0008948	79.90	gold quality
superficial temporal artery	UBERON:0001614	79.85	gold quality
lymph node	UBERON:0000029	79.77	gold quality
synovial joint	UBERON:0002217	79.66	gold quality
parietal pleura	UBERON:0002400	79.65	gold quality
lower lobe of lung	UBERON:0008949	79.45	gold quality
thoracic aorta	UBERON:0001515	79.37	gold quality
ascending aorta	UBERON:0001496	79.20	gold quality
rectum	UBERON:0001052	78.73	gold quality
smooth muscle tissue	UBERON:0001135	78.34	gold quality
adrenal gland	UBERON:0002369	77.83	gold quality
right coronary artery	UBERON:0001625	77.59	gold quality
pleura	UBERON:0000977	77.57	gold quality
left adrenal gland	UBERON:0001234	77.56	gold quality
caecum	UBERON:0001153	77.53	gold quality
colonic epithelium	UBERON:0000397	77.27	gold quality
left adrenal gland cortex	UBERON:0035825	76.91	gold quality
placenta	UBERON:0001987	76.88	gold quality
left coronary artery	UBERON:0001626	76.74	gold quality
lung	UBERON:0002048	76.43	gold quality
germinal epithelium of ovary	UBERON:0001304	76.42	gold quality
right adrenal gland cortex	UBERON:0035827	76.42	gold quality
medial globus pallidus	UBERON:0002477	76.38	gold quality
adrenal cortex	UBERON:0001235	75.79	gold quality
right adrenal gland	UBERON:0001233	75.50	gold quality
buccal mucosa cell	CL:0002336	75.43	gold quality
coronary artery	UBERON:0001621	75.42	gold quality
metanephros cortex	UBERON:0010533	75.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.15	gold quality
decidua	UBERON:0002450	75.14	gold quality
caudate nucleus	UBERON:0001873	74.94	gold quality
right atrium auricular region	UBERON:0006631	74.94	gold quality
aorta	UBERON:0000947	74.53	gold quality
visceral pleura	UBERON:0002401	74.39	gold quality
stromal cell of endometrium	CL:0002255	74.22	gold quality
left uterine tube	UBERON:0001303	74.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	74.20	gold quality
minor salivary gland	UBERON:0001830	74.09	gold quality
cardiac atrium	UBERON:0002081	73.94	gold quality
heart	UBERON:0000948	73.82	gold quality
amygdala	UBERON:0001876	73.73	gold quality
corpus callosum	UBERON:0002336	73.70	gold quality
thoracic mammary gland	UBERON:0005200	73.60	gold quality
urinary bladder	UBERON:0001255	73.56	gold quality
endothelial cell	CL:0000115	73.37	silver quality
mammary gland	UBERON:0001911	73.29	gold quality
heart left ventricle	UBERON:0002084	73.20	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	73.08	gold quality
apex of heart	UBERON:0002098	73.06	gold quality
globus pallidus	UBERON:0001875	73.01	gold quality
cardiac ventricle	UBERON:0002082	73.00	gold quality
lower esophagus muscularis layer	UBERON:0035833	72.98	gold quality
lower esophagus	UBERON:0013473	72.91	gold quality
mucosa of stomach	UBERON:0001199	72.82	gold quality
putamen	UBERON:0001874	72.74	gold quality
tendon of biceps brachii	UBERON:0008188	72.72	silver quality
nucleus accumbens	UBERON:0001882	72.61	gold quality
right lobe of thyroid gland	UBERON:0001119	72.42	gold quality
left lobe of thyroid gland	UBERON:0001120	72.31	gold quality
endometrium	UBERON:0001295	72.29	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	71.97	gold quality
heart right ventricle	UBERON:0002080	71.90	gold quality
thyroid gland	UBERON:0002046	71.67	gold quality
liver	UBERON:0002107	71.66	gold quality
skin of hip	UBERON:0001554	71.62	gold quality
mucosa of sigmoid colon	UBERON:0004993	71.58	gold quality
muscle of leg	UBERON:0001383	71.56	gold quality
tibial nerve	UBERON:0001323	71.31	gold quality
mammary duct	UBERON:0001765	71.31	gold quality
spinal cord	UBERON:0002240	71.17	gold quality
multicellular organism	UBERON:0000468	71.13	gold quality
material anatomical entity	UBERON:0000465	71.10	gold quality
anatomical system	UBERON:0000467	71.07	gold quality
popliteal artery	UBERON:0002250	71.05	gold quality
gastrocnemius	UBERON:0001388	71.04	gold quality
tibial artery	UBERON:0007610	71.03	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.57
E-MTAB-9801	yes	6.09
E-GEOD-124858	no	256.55

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Spleen	tissue	30.7	medium
Adipose tissue	tissue	29.1	not detected
Hippocampus	tissue	28.7	not detected
Nucleus accumbens	tissue	27.7
Locus coeruleus	tissue	26.0
Appendix	tissue	24.3	not detected
Placenta	tissue	22.5	not detected
Bone marrow	tissue	21.0	high
Liver	tissue	15.6	not detected
Lung	tissue	15.3	not detected
Postcentral gyrus	tissue	14.4
Urinary bladder	tissue	12.4	not detected
Lymph node	tissue	12.3	medium
Tongue	tissue	11.2
Choroid plexus	tissue	10.9
Adrenal gland	tissue	10.4	low
Smooth muscle	tissue	10.1	not detected
Gallbladder	tissue	10.1	not detected
Heart muscle	tissue	7.8	not detected
Hypothalamus	tissue	7.6
Septum	tissue	7.3
Tonsil	tissue	7.2	low
Rectum	tissue	6.8	not detected
Breast	tissue	6.7	not detected
Colon	tissue	6.3	not detected
Kidney	tissue	6.3	not detected
Cervix	tissue	6.1	not detected
Ovary	tissue	6.0	not detected
Periaqueductal gray	tissue	5.9
Pons	tissue	5.6
Spinal cord	tissue	5.6
Substantia nigra	tissue	5.5
Small intestine	tissue	5.4	not detected
Endometrium 1	tissue	5.2	not detected
Amygdala	tissue	5.2
Hippocampal formation	tissue	5.2
Entorhinal cortex	tissue	5.0
Esophagus	tissue	4.5	low
Putamen	tissue	4.5
Ventral forebrain	tissue	4.5
Thyroid gland	tissue	4.3	not detected
Prostate	tissue	4.3	not detected
Stomach 1	tissue	4.2	not detected
Cerebral cortex	tissue	4.2	low
Basal ganglia	tissue	4.2	not detected
Temporal cortex	tissue	4.2
Motor cortex	tissue	4.1
Insular cortex	tissue	4.1
Prefrontal cortex	tissue	4.0
Duodenum	tissue	4.0	not detected
Midbrain	tissue	3.9
Thalamus	tissue	3.9
Fallopian tube	tissue	3.9	not detected
Superior colliculi	tissue	3.8
Medulla oblongata	tissue	3.7
Retrosplenial and cingulate cortex	tissue	3.5
Retrosplenial cortex	tissue	3.5
Thymus	tissue	3.3
Somatosensory cortex	tissue	3.2
Occipital cortex	tissue	3.2

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Supraoptic nucleus (45.5), Globus pallidus, externus (39.9), Cervical spinal cord, ventral horn (39.5), Dorsal raphe nucleus (37.6), Centromedial thalamic nucleus (36.8).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets:

Target	Regulation
CCL5	Activation
CXCL1	Activation
CXCL2	Activation
IL1B	Activation
IL6	Activation
LGALS9	Activation
TNF	Activation

Upstream regulators (CollecTRI, top): AP1, ATF3, CDX2, CEBPD, FOS, FOXO1, HIF1A, IRF3, IRF4, IRF6, IRF8, NFKB, NR1D1, NR1H3, PPARA, PPARG, SP1, SPI1, STAT3, STAT6, ZNF160

miRNA regulators (miRDB)

Targeting TLR4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 95 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-153-5P	99.89	73.86	6317

Functional genomics

gnomAD constraint: pLI 0.000411, LOEUF 0.858, missense Z 1.01 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000355622 — one region, missense o/e 0.96.

Literature-anchored findings (GeneRIF, showing 40)

• Intestinal epithelial cells express very low levels of Toll-like receptor-4 by a mechanism which protects them against dysregulated proinflammatory signaling in response to Gram-negative commensal bacteria and their products. (PMID:11466383)
• A TLR4 agonist specifically promoted the production of the Th1-inducing cytokine interleukin (IL) 12 p70 and the chemokine interferon-gamma inducible protein (IP)-10. (PMID:11477091)
• downregulation on gingival fibroblasts by Porphyromonas gingivalis lipopolysaccharide (PMID:11688988)
• LPS may activate a mammalian serine protease, which generates a product required for TLR4 signalling (PMID:11728442)
• identification of role in novel signal transduction pathway utilized by exracellular HSP70 (PMID:11836257)
• regulation of TLR4 surface expression in human peripheral blood monocytes and B cells by interleukin-2 (IL-2) and IL-4 (PMID:11841848)
• stimulation of signal pathway by HSP70 (PMID:11842086)
• signaling events by TLR2 and TLR4 agonists are similar but there are distinct differences in the responses elicited by two bacterial products (PMID:11877429)
• sequence polymorphism in the gene causes an endotoxin-hyporesponsive phenotype in humans (PMID:11893689)
• expression regulated by immune-mediated signals in intestinal epithelial cells (PMID:11923281)
• The extracellular, but not cytoplasmic domain of TLR1 inhibits Toll-like receptor 4 signaling in endothelial cells. TLR1 might restrain the dangerous innate response to LPS by binding to TLR4 and preventing the formation of active signaling complexes. (PMID:11932926)
• Though TLR4 binds bacterial lipopolysaccharides, it had no role in binding non-lipopolysaccharide components from C. pneumoniae. (PMID:11932927)
• interferon-gamma augmented mRNA and surface expression of TLR4 in monocytes and macrophages (PMID:11964313)
• involvement in cell activation by mannuronic acid polymers (PMID:12089142)
• bacterium-induced CXCL10 secretion by osteoblast can be mediated in part through toll-like receptor 4 (PMID:12117914)
• The Asp299Gly TLR4 polymorphism is associated with a decreased risk of atherosclerosis. (PMID:12124407)
• Hypoxia decreases TLR4 expression in endothelial cells and this change is mediated by mitochondrial ROS leading to attenuation of AP-1 transcriptional activity. (PMID:12165534)
• Data show that the TLR4-mediated LPS response in bladder epithelial cells also uses the co-receptor CD14 for efficient LPS signalling. (PMID:12174084)
• According to the present results an allelic variation in the TLR4 receptor was associated with increased risk of premature birth. (PMID:12193670)
• Susceptibility of human dendritic cells (DCs) to measles virus (MV) depends on their activation stages in conjunction with the level of CDw150: role of Toll stimulators in DC maturation and MV amplification (PMID:12270725)
• Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex (PMID:12324469)
• Although expression levels of TLR4 mRNA and protein are normal in lipopolysaccharide (LPS)-tolerant monocytes, association of TLR4 with MyD88 is inhibited by LPS restimulation. (PMID:12391239)
• We conclude that the CARD15 mutation and hyporesponsive TLR4 allele do not contribute to ethnic variation in the incidence of PPROM. (PMID:12397216)
• role of polymorphism in susceptibility to Candida albicans infection (PMID:12402214)
• Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes. (PMID:12406828)
• lipopolysaccharide may induce proliferation of periodontal epithelial cells by upregulating keratinocyte growth factor 1 expression via the CD14 and Toll-like receptor signaling pathway (PMID:12438323)
• LPS-induced NF-kappaB activation and IL-8 gene expression use a signaling pathway requiring protein tyrosine kinase and that such regulation may occur through tyrosine phosphorylation of TLR4. (PMID:12495941)
• TLR2 and TLR4 mRNA were significantly up-regulated by IL-10 in monocyte cells that were adherent compared to those nonadherent. (PMID:12525572)
• participates in the innate immune response to stimulation by bacterial products in periodontal tissues (PMID:12588460)
• Expressed in immortalized human liver cell lines (PMID:12591474)
• These data indicate that Toll-like receptor 4 modulation of polymorphonuclear leukocyte (PMN) surface chemokine receptor expression is a critical determinant of PMN migration. (PMID:12592402)
• innate immune recognition of LTA via LBP, CD14, and TLR-2 represents an important mechanism in the pathogenesis of systemic complications in the course of infectious diseases brought about by Gram-positive pathogens. while TLR-4 and MD-2 are not involved. (PMID:12594207)
• findings indicate that, although the gastric epithelium is important in directing the immune response against H. pylori infections, the response is independent of TLR4 (PMID:12599057)
• Mutations in the gene for toll-like receptor 4 and multiple sclerosis (PMID:12622779)
• Review. TLR4 signaling is intimately involved in anti-cancer immunity induced by immunopotentiators. Our clinical examination in oral cancer patients also suggests the requirement of both TLR4 and MD-2 in the OK-432-induced anti-cancer host response. (PMID:12630564)
• human activated hepatic stellate cells utilize components of TLR4 signal transduction cascade to stimulate NF-kappaB and JNK and up-regulate chemokines and adhesion molecules. (PMID:12717385)
• TLR4 activation of NFkappaB requires Bruton’s tyrosine kinase (PMID:12724322)
• Assay of locus-specific genetic load implicates mutations in this receptor in meningococcal susceptibility. (PMID:12730365)
• First comparative investigation in highly purified, monocyte-depleted neutrophil populations shows a distinct and separate role for TLR4, compared with TLR2, in neutrophil responses and neutrophil survival. (PMID:12734376)
• TLR4 is able to undergo multiple glycosylations without MD-2 but that the specific glycosylation essential for cell surface expression requires the presence of MD-2. (PMID:12738639)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tlr4	ENSMUSG00000039005
rattus_norvegicus	Tlr4	ENSRNOG00000010522

Paralogs (22): IGFALS (ENSG00000099769), TLR8 (ENSG00000101916), LRRC17 (ENSG00000128606), RXFP2 (ENSG00000133105), CD180 (ENSG00000134061), TLR2 (ENSG00000137462), LRRC32 (ENSG00000137507), LRRC3 (ENSG00000160233), LRRC53 (ENSG00000162621), TLR3 (ENSG00000164342), VASN (ENSG00000168140), RXFP1 (ENSG00000171509), NRROS (ENSG00000174004), TLR10 (ENSG00000174123), TLR1 (ENSG00000174125), TLR6 (ENSG00000174130), LRRC3B (ENSG00000179796), TSKU (ENSG00000182704), TLR5 (ENSG00000187554), TLR7 (ENSG00000196664), LRIT2 (ENSG00000204033), LRRC3C (ENSG00000204913)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:96824) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 128 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased tumor necrosis factor secretion	8
increased susceptibility to bacterial infection	7
decreased macrophage cytokine production	5
abnormal macrophage physiology	3
decreased susceptibility to injury	3
decreased interleukin-1 beta secretion	3
abnormal tumor necrosis factor level	3
cellular necrosis	2
abnormal respiratory system physiology	2
decreased incidence of tumors by chemical induction	2
decreased cerebral infarct size	2
decreased interleukin-6 secretion	2
decreased susceptibility to endotoxin shock	2
increased cell death	2
increased bone mineral density	1
abnormal circulating glucose level	1
abnormal cecum morphology	1
abnormal hepatocyte morphology	1
abnormal liver physiology	1
abnormal retina rod cell morphology	1
abnormal uterus morphology	1
decreased body weight	1
decreased body size	1
abnormal locomotor behavior	1
abnormal motor coordination/balance	1

+103 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gorilla gorilla gorilla	B3Y615	99.9%	Diamond
Pan troglodytes	B3Y613	99.7%	Diamond
Pan paniscus	B3Y614	99.7%	Diamond
Macaca mulatta	B3Y618	99.2%	Diamond
Macaca fascicularis	Q95M53	99.2%	Diamond
Bos indicus	B5T267	98.1%	Diamond
Bos taurus	Q95LA9	98.1%	Diamond
Capra ibex	B2LT62	98.0%	Diamond
Ovis aries	B2LT65	98.0%	Diamond
Bubalus bubalis	Q2PZH4	97.8%	Diamond
Bison bison	B2LT61	97.6%	Diamond
Boselaphus tragocamelus	Q2V897	97.1%	Diamond
Capra hircus	Q0GC71	96.8%	Diamond
Pongo pygmaeus	Q8SPE9	93.3%	Diamond
Papio anubis	Q9TSP2	93.3%	Diamond
Giraffa camelopardalis	B2LT64	91.2%	Diamond
Cricetulus griseus	Q9R1F8	83.9%	Diamond
Gallus gallus	Q9DD78	83.2%	Diamond
Canis lupus familiaris	Q689D1	83.1%	Diamond
Equus caballus	Q6T752	82.3%	Diamond
Felis catus	P58727	81.2%	Diamond
Sus scrofa	Q68Y56	76.1%	Diamond
Danio rerio	A8WHP9	58.8%	Diamond
Drosophila melanogaster	Q9V477	49.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ASTN2	protein-coding	23245

Protein

Protein identifiers

Toll-like receptor 4 — O00206 (reviewed: O00206)

Alternative names: hToll

All UniProt accessions (2): A0A2R8Y7P4, O00206

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane receptor that functions as a pattern recognition receptor recognizing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) to induce innate immune responses via downstream signaling pathways. At the plasma membrane, cooperates with LY96 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Mechanistically, acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Alternatively, CD14-mediated TLR4 internalization via endocytosis is associated with the initiation of a MYD88-independent signaling via the TICAM1-TBK1-IRF3 axis leading to type I interferon production. In addition to the secretion of proinflammatory cytokines, initiates the activation of NLRP3 inflammasome and formation of a positive feedback loop between autophagy and NF-kappa-B signaling cascade. In complex with TLR6, promotes inflammation in monocytes/macrophages by associating with TLR6 and the receptor CD86. Upon ligand binding, such as oxLDL or amyloid-beta 42, the TLR4:TLR6 complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway. In myeloid dendritic cells, vesicular stomatitis virus glycoprotein G but not LPS promotes the activation of IRF7, leading to type I IFN production in a CD14-dependent manner. Required for the migration-promoting effects of ZG16B/PAUF on pancreatic cancer cells.

Subunit / interactions. Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4. Binding to bacterial LPS leads to homodimerization. Interacts with LY96 via the extracellular domain. Interacts with MYD88. Interacts (via TIR domains) with TIRAP. Interacts with TICAM2. Interacts with NOX4. Interacts with CNPY3. Interacts with HSP90B1. The interaction with both CNPY3 and HSP90B1 is required for proper folding in the endoplasmic reticulum. Interacts with MAP3K21; this interaction leads to negative regulation of TLR4 signaling. Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6. The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Interacts with TICAM1 in response to LPS in a WDFY1-dependent manner. Interacts with WDFY1 in response to LPS. Interacts with SMPDL3B. Interacts with CEACAM1; upon lipopolysaccharide stimulation, forms a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome. Interacts with RFTN1; the interaction occurs in response to lipopolysaccharide stimulation. Interacts with SCIMP; the interaction occurs in response to lipopolysaccharide stimulation and is enhanced by phosphorylation of SCIMP by LYN. This interaction facilitates the phosphorylation of TLR4 by LYN which elicits a selective cytokine response in macrophages. Interacts with TRAF3IP3. Interacts with TREM1; this interaction enhances TLR4-mediated inflammatory response. Interacts with ZG16B/PAUF. Interacts with CD82; this interaction inhibits TLR4-mediated signaling pathway. Interacts with neutrophil recruitment protein from Aedes aegypti saliva; the interaction probably promotes activation of canonical NF-kappa-B signaling in skin-resident macrophages and subsequent expression of neutrophil chemoattractants. Interacts with CD180; this interaction inhibits TLR4-mediated signaling pathway upon ligand binding. (Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC. (Microbial infection) In case of infection, interacts with B.melitensis protein TcpB; TcpB abolishes the TLR4-TIRAP interaction in vitro. (Microbial infection) Interacts with ebolavirus protein GP; this interaction leads to the production of proinflammatory cytokines and suppressor of cytokine signaling 1/SOCS1.

Subcellular location. Cell membrane. Early endosome. Cell projection. Ruffle.

Tissue specificity. Highly expressed in placenta, spleen and peripheral blood leukocytes. Detected in monocytes, macrophages, dendritic cells and several types of T-cells. Expressed in pancreatic cancer cells but not in normal pancreatic cells (at protein level).

Post-translational modifications. N-Glycosylation of Asn-526 and Asn-575 by STT3A-containing OST-A complex is necessary for the expression of TLR4 on the cell surface and the LPS-response. Likewise, mutants lacking two or more of the other N-glycosylation sites were deficient in interaction with LPS. Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide. Ubiquitinated by RNF128 via ‘Lys-28’-linked polyubiquitin chains, leading to proteasomal degradation.

Domain organisation. The TIR domain mediates interaction with NOX4.

Induction. By LPS in plasmacytoid dendritic cells.

Polymorphism. Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS.

Miscellaneous. His-456 and His-458 are found in TLR4 of human and several other primate species and may be responsible for inflammatory responses triggered by nickel (Ni(2+)). Ni(2+) may cross-link the two receptor monomers through specific histidines, triggering the formation of a dimer that structurally resembles that induced by LPS. This process may be the basis for the development of contact allergy to Ni(2+). A mouse model of contact allergy to Ni(2+) in which TLR4-deficient mice expresses human TLR4 has been proposed.

Similarity. Belongs to the Toll-like receptor family.

Isoforms (3)

UniProt ID	Names	Canonical?
O00206-1	1	yes
O00206-2	2
O00206-3	3

RefSeq proteins (3): NP_003257, NP_612564, NP_612567 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000157	TIR_dom	Domain
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR017241	Toll-like_receptor	Family
IPR025875	Leu-rich_rpt_4	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR035897	Toll_tir_struct_dom_sf	Homologous_superfamily

Pfam: PF01582, PF12799, PF13516, PF13855

UniProt features (143 total): strand 39, helix 21, repeat 18, sequence variant 18, turn 11, glycosylation site 10, mutagenesis site 9, disulfide bond 5, sequence conflict 3, topological domain 2, domain 2, splice variant 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

15 structures by resolution:

PDB	Title	Method	Resolution (Å)
2Z62	Crystal structure of the TV3 hybrid of human TLR4 and hagfish VLRB.61	X-RAY DIFFRACTION	1.7
2Z66	Crystal structure of the VT3 hybrid of human TLR4 and hagfish VLRB.61	X-RAY DIFFRACTION	1.9
2Z63	Crystal structure of the TV8 hybrid of human TLR4 and hagfish VLRB.61	X-RAY DIFFRACTION	2
8WO1	Cryo-EM Structure of Human TLR4/MD-2/DLAM5 Complex	ELECTRON MICROSCOPY	2.24
3UL7	Crystal structure of the TV3 mutant F63W	X-RAY DIFFRACTION	2.37
4G8A	Crystal structure of human TLR4 polymorphic variant D299G and T399I in complex with MD-2 …	X-RAY DIFFRACTION	2.4
3UL9	structure of the TV3 mutant M41E	X-RAY DIFFRACTION	2.45
3UL8	Crystal structure of the TV3 mutant V134L	X-RAY DIFFRACTION	2.5
2Z65	Crystal structure of the human TLR4 TV3 hybrid-MD-2-Eritoran complex	X-RAY DIFFRACTION	2.7
9J03	Cyro-EM Structure of Human TLR4/MD-2/DLAM1 Complex	ELECTRON MICROSCOPY	2.7
8WTA	Cryo-EM Structure of Human TLR4/MD-2/DLAM3 Complex	ELECTRON MICROSCOPY	2.9
3FXI	Crystal structure of the human TLR4-human MD-2-E.coli LPS Ra complex	X-RAY DIFFRACTION	3.1
3ULA	Crystal structure of the TV3 mutant F63W-MD-2-Eritoran complex	X-RAY DIFFRACTION	3.6
5NAM	NMR structure of TLR4 transmembrane domain (624-670) in DMPG/DHPC bicelles	SOLUTION NMR
5NAO	NMR structure of TLR4 transmembrane domain (624-657) in DPC micelles	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00206-F1	89.42	0.71

Human Protein Atlas

Protein class: CD markers, Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted intracellular proteins, FDA approved drug targets, Small molecule drugs, Human disease related genes, Eye disease

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus; plasma membrane

Antibody reliability (HPA): IH approved · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (5)

Type	Positions
Disulfide bond	29–40, 281–306, 390–391, 583–609, 585–627

Glycosylation sites (10)

Type	Positions
N-linked (glcnac…) asparagine	35, 173, 205, 282, 309, 497, 526, 575, 624, 630

Mutagenesis-validated functional residues (9)

Position	Phenotype
431	partially diminishes nf-kappa-b activation induced by ni(2+). strongly reduces nf-kappa-b activation induced by ni(2+); when associated …
456	partially diminishes nf-kappa-b activation induced by ni(2+). strongly reduces nf-kappa-b activation induced by ni(2+); when associated …
458	partially diminishes nf-kappa-b activation induced by ni(2+). strongly reduces nf-kappa-b activation induced by ni(2+); when associated …
526	abolishes lps-response and prevents the cell surface expression.
575	abolishes lps-response and prevents the cell surface expression.
697	abolishes lps-response.
710	abolishes lps-response.
711	abolishes lps-response.
714	abolishes myd88-binding and lps-response.

Function

Pathways and Gene Ontology

Reactome pathways

18 curated (TAS) of 43; 11 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

43 pathways:

ID	Pathway	Evidence
R-HSA-9918481	Dengue Virus-Host Interactions ⚕	curated
R-HSA-5603041	IRAK4 deficiency (TLR2/4) ⚕	curated
R-HSA-5602498	MyD88 deficiency (TLR2/4) ⚕	curated
R-HSA-9833110	RSV-host interactions ⚕	curated
R-HSA-9820960	Respiratory syncytial virus (RSV) attachment and entry ⚕	curated
R-HSA-936964	Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	curated
R-HSA-140534	Caspase activation via Death Receptors in the presence of ligand	curated
R-HSA-1236974	ER-Phagosome pathway	curated
R-HSA-9707616	Heme signaling	curated
R-HSA-937041	IKK complex recruitment mediated by RIP1	curated
R-HSA-975163	IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation	curated
R-HSA-166166	MyD88-independent TLR4 cascade	curated
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane	curated
R-HSA-9824878	Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7	curated
R-HSA-5686938	Regulation of TLR by endogenous ligand	curated
R-HSA-937072	TRAF6-mediated induction of TAK1 complex within TLR4 complex	curated
R-HSA-2562578	TRIF-mediated programmed cell death	curated
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5602358	Diseases associated with the TLR signaling cascade ⚕	—
R-HSA-5260271	Diseases of Immune System ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9820952	Respiratory Syncytial Virus Infection Pathway ⚕	—
R-HSA-9824446	Viral Infection Pathways ⚕	—
R-HSA-1280218	Adaptive Immune System	—
R-HSA-1236975	Antigen processing-Cross presentation	—
R-HSA-109581	Apoptosis	—
R-HSA-5357769	Caspase activation via extrinsic apoptotic signalling pathway	—
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-983169	Class I MHC mediated antigen processing & presentation	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-975155	MyD88 dependent cascade initiated on endosome	—
R-HSA-5357801	Programmed Cell Death	—
R-HSA-975138	TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	—
R-HSA-937061	TRIF (TICAM1)-mediated TLR4 signaling	—
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade	—
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade	—
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade	—
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade	—
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade	—
R-HSA-168898	Toll-like Receptor Cascades	—

MSigDB gene sets: 781 (showing top): REACTOME_TRAF6_MEDIATED_INDUCTION_OF_TAK1_COMPLEX_WITHIN_TLR4_COMPLEX, GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_IKK_COMPLEX_RECRUITMENT_MEDIATED_BY_RIP1, GOBP_CELLULAR_RESPONSE_TO_LIPOPROTEIN_PARTICLE_STIMULUS, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_DIGESTION, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, GOBP_CARTILAGE_DEVELOPMENT

GO Biological Process (64): toll-like receptor signaling pathway (GO:0002224), wound healing involved in inflammatory response (GO:0002246), MyD88-dependent toll-like receptor signaling pathway (GO:0002755), phagocytosis (GO:0006909), inflammatory response (GO:0006954), immune response (GO:0006955), positive regulation of platelet activation (GO:0010572), positive regulation of gene expression (GO:0010628), detection of fungus (GO:0016046), lipopolysaccharide-mediated signaling pathway (GO:0031663), response to lipopolysaccharide (GO:0032496), detection of lipopolysaccharide (GO:0032497), negative regulation of type II interferon production (GO:0032689), negative regulation of interleukin-17 production (GO:0032700), negative regulation of interleukin-23 production (GO:0032707), negative regulation of interleukin-6 production (GO:0032715), negative regulation of tumor necrosis factor production (GO:0032720), positive regulation of chemokine production (GO:0032722), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-1 production (GO:0032732), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), positive regulation of tumor necrosis factor production (GO:0032760), toll-like receptor 4 signaling pathway (GO:0034142), TRIF-dependent toll-like receptor signaling pathway (GO:0035666), cellular response to platelet-derived growth factor stimulus (GO:0036120), T-helper 1 type immune response (GO:0042088), macrophage activation (GO:0042116), defense response to bacterium (GO:0042742), positive regulation of macrophage activation (GO:0043032), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), innate immune response (GO:0045087), positive regulation of nitric oxide biosynthetic process (GO:0045429), negative regulation of osteoclast differentiation (GO:0045671), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of inflammatory response (GO:0050729), defense response to Gram-negative bacterium (GO:0050829), intestinal epithelial structure maintenance (GO:0060729), negative regulation of ERK1 and ERK2 cascade (GO:0070373), cellular response to lipopolysaccharide (GO:0071222), cellular response to mechanical stimulus (GO:0071260), cellular response to type II interferon (GO:0071346), negative regulation of cold-induced thermogenesis (GO:0120163), cellular response to oxidised low-density lipoprotein particle stimulus (GO:0140052), positive regulation of cytokine production involved in inflammatory response (GO:1900017), positive regulation of NLRP3 inflammasome complex assembly (GO:1900227), positive regulation of reactive oxygen species biosynthetic process (GO:1903428), positive regulation of cellular response to macrophage colony-stimulating factor stimulus (GO:1903974), positive regulation of matrix metallopeptidase secretion (GO:1904466), cellular response to amyloid-beta (GO:1904646), positive regulation of chemokine (C-X-C motif) ligand 2 production (GO:2000343), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), immune system process (GO:0002376), defense response (GO:0006952), signal transduction (GO:0007165)

+4 more (showing top 60).

GO Molecular Function (9): lipopolysaccharide binding (GO:0001530), amyloid-beta binding (GO:0001540), lipopolysaccharide immune receptor activity (GO:0001875), transmembrane signaling receptor activity (GO:0004888), signaling receptor binding (GO:0005102), signaling receptor activity (GO:0038023), identical protein binding (GO:0042802), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (12): ruffle (GO:0001726), phagocytic cup (GO:0001891), cytoplasm (GO:0005737), early endosome (GO:0005769), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), endosome membrane (GO:0010008), signaling receptor complex (GO:0043235), lipopolysaccharide receptor complex (GO:0046696), perinuclear region of cytoplasm (GO:0048471), membrane (GO:0016020)

Reactome top-level categories

15 top-level categories:

Category	Pathways
TRIF (TICAM1)-mediated TLR4 signaling	4
Toll-like Receptor Cascades	2
Toll Like Receptor 4 (TLR4) Cascade	2
Diseases associated with the TLR signaling cascade	2
Respiratory Syncytial Virus Infection Pathway	2
Antigen processing-Cross presentation	1
Caspase activation via extrinsic apoptotic signalling pathway	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Cellular responses to stress	1
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1
Dengue Virus Infection	1
Programmed Cell Death	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

showing 60 of 71 GO namespaces:

Category	Terms
cellular anatomical structure	5
negative regulation of cytokine production	4
positive regulation of type I interferon production	2
protein binding	2
plasma membrane	2
endosome	2
pattern recognition receptor signaling pathway	1
inflammatory response	1
wound healing	1
inflammatory response to wounding	1
toll-like receptor signaling pathway	1
endocytosis	1
defense response	1
immune system process	1
response to stimulus	1
regulation of platelet activation	1
platelet activation	1
positive regulation of cell activation	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
response to fungus	1
detection of other organism	1
cell surface receptor signaling pathway	1
cellular response to lipopolysaccharide	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
detection of molecule of bacterial origin	1
response to lipopolysaccharide	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-17 production	1
regulation of interleukin-17 production	1
interleukin-23 production	1
regulation of interleukin-23 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
positive regulation of cytokine production	1
chemokine production	1
regulation of chemokine production	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interferon-beta production	1
regulation of interferon-beta production	1
lipid binding	1
carbohydrate derivative binding	1
peptide binding	1
lipopolysaccharide binding	1
lipopolysaccharide-mediated signaling pathway	1
pattern recognition receptor activity	1
signaling receptor activity	1
molecular transducer activity	1
protein dimerization activity	1
binding	1
cell leading edge	1
plasma membrane bounded cell projection	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 45 of 85 annotations. The rest are phylogenetic / computational / electronic (IEA).

45 experimentally-supported GO terms:

GO term	NS	Evidence
MyD88-dependent toll-like receptor signaling pathway	BP	direct assay
cellular response to amyloid-beta	BP	direct assay
cellular response to lipopolysaccharide	BP	direct assay
cellular response to mechanical stimulus	BP	expression pattern
cellular response to oxidised low-density lipoprotein particle stimulus	BP	direct assay
cellular response to type II interferon	BP	direct assay
defense response to bacterium	BP	genetic interaction
detection of lipopolysaccharide	BP	direct assay
inflammatory response	BP	direct assay
lipopolysaccharide-mediated signaling pathway	BP	genetic interaction
macrophage activation	BP	mutant phenotype
phagocytosis	BP	direct assay
positive regulation of canonical NF-kappaB signal transduction	BP	direct assay
positive regulation of cellular response to macrophage colony-stimulating factor stimulus	BP	direct assay
positive regulation of chemokine (C-X-C motif) ligand 2 production	BP	mutant phenotype
positive regulation of chemokine production	BP	direct assay
positive regulation of cytokine production involved in inflammatory response	BP	direct assay
positive regulation of gene expression	BP	mutant phenotype
positive regulation of inflammatory response	BP	direct assay
positive regulation of interleukin-1 beta production	BP	direct assay
positive regulation of interleukin-12 production	BP	direct assay
positive regulation of interleukin-6 production	BP	direct assay
positive regulation of interleukin-8 production	BP	direct assay
positive regulation of matrix metallopeptidase secretion	BP	mutant phenotype
positive regulation of transcription by RNA polymerase II	BP	direct assay
positive regulation of tumor necrosis factor production	BP	direct assay
response to lipopolysaccharide	BP	direct assay
toll-like receptor 4 signaling pathway	BP	direct assay
toll-like receptor signaling pathway	BP	direct assay
cell surface	CC	direct assay
cytoplasm	CC	direct assay
endosome membrane	CC	direct assay
external side of plasma membrane	CC	direct assay
lipopolysaccharide receptor complex	CC	direct assay
perinuclear region of cytoplasm	CC	direct assay
phagocytic cup	CC	direct assay
plasma membrane	CC	direct assay
signaling receptor complex	CC	physical interaction
identical protein binding	MF	physical interaction
lipopolysaccharide binding	MF	mutant phenotype
lipopolysaccharide immune receptor activity	MF	direct assay
protein heterodimerization activity	MF	physical interaction
signaling receptor activity	MF	direct assay
signaling receptor binding	MF	physical interaction
transmembrane signaling receptor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 5,887 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLR4	IL1B	P01584	963
TLR4	IL6	P05231	962
TLR4	TNF	P01375	959
TLR4	LY96	Q9Y6Y9	945
TLR4	IL10	P22301	939
TLR4	IFNG	P01579	936
TLR4	NFKB1	P19838	929
TLR4	IL18	Q14116	903
TLR4	TRAF6	Q9Y4K3	901
TLR4	IRAK1	P51617	896
TLR4	IL1R1	P14778	894
TLR4	IFNB1	P01574	893
TLR4	IL1A	P01583	890
TLR4	CXCL8	P10145	881
TLR4	IRF3	Q14653	881

IntAct

Human interaction partners of TLR4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

27 partners by confidence:

Partner	Interaction type	MIscore	Records
TIRAP	physical association	0.810	6
MYD88	physical association	0.760	2
LY96	physical association	0.740	5
NOX4	physical association	0.680	4
TICAM2	physical association	0.680	2
HMGB1	physical association	0.600	3
MBL2	direct interaction	0.560	2
TNC	direct interaction	0.540	4
SIGLEC5	physical association	0.540	2
SIGLEC6	physical association	0.540	2
SIGLEC9	physical association	0.540	2
TLR6	physical association	0.500	1
BGN	direct interaction	0.440	1
FCN1	direct interaction	0.440	1
FGG	direct interaction	0.440	1
SIGLEC11	direct interaction	0.440	1
SIGLEC7	direct interaction	0.440	1
TNN	direct interaction	0.440	1
TNR	direct interaction	0.440	1
ADIPOR1	physical association	0.400	2
EGFR	physical association	0.400	1
F2RL1	physical association	0.400	1
ZG16B	physical association	0.400	1
SERTAD1	physical association	0.370	1
SMAD3	physical association	0.370	1
CD36	association	0.350	1
TRAF3	association	0.350	1

BioGRID (87 interactions; top human partners by supporting records): MYD88 (Two-hybrid; 9 records), TIRAP (Affinity Capture-Western; 9 records), TICAM2 (Affinity Capture-Western; 5 records), TRAF3 (Affinity Capture-Western; 5 records), TRIM44 (Affinity Capture-Western; 4 records), SRC (Affinity Capture-Western; 3 records), TICAM1 (Affinity Capture-Western; 3 records), CAV1 (Affinity Capture-Western; 2 records), HGS (Affinity Capture-Western; 2 records), LY96 (Affinity Capture-Western; 2 records), MFN1 (Affinity Capture-Western; 2 records), NPM1 (Affinity Capture-Western; 2 records), RNF216 (Two-hybrid; 2 records), TOLLIP (Affinity Capture-Western; 2 records), TRAF6 (Affinity Capture-Western; 2 records)

SIGNOR signaling

25 signaling interactions:

A	Effect	B	Mechanism
TLR4	up-regulates	TIRAP	binding
TLR4	up-regulates	TICAM2	binding
TLR4	up-regulates	Immune_response
TLR4	up-regulates	Interferon_Production
TLR4	up-regulates	TLR4	binding
PAMPs	“up-regulates activity”	TLR4
TLR4	“up-regulates activity”	NfKb-p65/p50
TLR4	“up-regulates activity”	JUN
FCGR2B	“down-regulates activity”	TLR4
HMGB1	“up-regulates activity”	TLR4	binding
TLR4	“up-regulates activity”	TIRAP	binding
S100A9	“up-regulates activity”	TLR4	binding
S100A8	“down-regulates activity”	TLR4	binding
TLR4	up-regulates	Differentiation
TLR4	“up-regulates activity”	p38	phosphorylation
TLR4	“up-regulates activity”	JNK	phosphorylation
TLR4	“up-regulates activity”	ERK1/2	phosphorylation
TLR4	“up-regulates activity”	MAPK14	phosphorylation
RNF216	“down-regulates quantity by destabilization”	TLR4	ubiquitination
SRC	“up-regulates activity”	TLR4	phosphorylation
TLR4	“up-regulates activity”	MYD88	binding
TLR4	“up-regulates activity”	TLR4	binding
TLR4	“up-regulates activity”	TICAM1	binding
lipopolysaccharide	“up-regulates activity”	TLR4	“chemical activation”
TLR4	“up-regulates activity”	MAP3K8

Protein complexes (CORUM) (10)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

10 complexes by size:

Complex	Subunits	Members
★ IRAK1-MYD88-SYK-TLR4 complex	4	MYD88, SYK, TLR4, IRAK1
★ SCIMP-SYK-TLR4 complex	3	SYK, TLR4, SCIMP
TICAM1-TICAM2-TLR4 complex	3	TICAM1, TICAM2, TLR4
MYD88-TIRAP-TLR4 complex	3	MYD88, TIRAP, TLR4
LPS receptor complex	3	CD14, LY96, TLR4
CD36-TLR4-TLR6 complex	3	CD36, TLR4, TLR6
★ MyD88-SYK-TLR4 complex	3	MYD88, SYK, TLR4
LY96-TLR4 complex	2	LY96, TLR4
TLR4-TLR5 complex	2	TLR4, TLR5
MYD88-TLR4 complex	2	MYD88, TLR4

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
MyD88 deficiency (TLR2/4)	7	175.3×	6e-13
IRAK4 deficiency (TLR2/4)	7	166.5×	6e-13
Regulation of TLR by endogenous ligand	5	103.4×	4e-08
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	7	44.4×	1e-08
ER-Phagosome pathway	7	37.9×	2e-08
Adaptive Immune System	7	8.7×	2e-04
Innate Immune System	6	6.4×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of toll-like receptor 4 signaling pathway	5	183.6×	2e-08
toll-like receptor 4 signaling pathway	5	97.5×	2e-07
positive regulation of interleukin-1 beta production	6	57.6×	2e-07
positive regulation of interleukin-8 production	5	45.2×	6e-06
positive regulation of interleukin-6 production	6	37.1×	1e-06
positive regulation of tumor necrosis factor production	5	28.4×	3e-05
positive regulation of ERK1 and ERK2 cascade	7	22.1×	2e-06
cellular response to lipopolysaccharide	5	18.1×	2e-04

Disease & clinical

Genetic variants

Variant evidence for TLR4: 124 ClinVar records (0 pathogenic / likely pathogenic); 6 PharmGKB clinical annotations; 48 GWAS associations.

ClinVar

124 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	84
Likely benign	21
Benign	7

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 17 predictions of 251):

Position(s)	Effect	Δscore	Sites
9:117704566–117704567	donor_loss	1.0000	3
9:117704566	donor_loss	0.9800
9:117704566	donor_loss	0.9700
9:117705397	donor_gain	0.9200
9:117714585	donor_gain	0.8400
9:117712387–117712388	acceptor_loss	0.8100	6
9:117712380	acceptor_loss	0.8000
9:117712386	acceptor_loss	0.8000
9:117714654	donor_gain	0.7700
9:117705375	donor_gain	0.7300

AlphaMissense

1,422 missense substitutions predicted likely pathogenic (of 5,580 scored), across 384 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F712	8	0.979	0.999
F677	8	0.972	0.998
D711	8	0.956	0.991
F807	8	0.949	0.992
F741	8	0.946	0.995
F749	8	0.938	0.992
D453	8	0.936	0.977
D675	8	0.935	0.989
N112	8	0.917	0.980
S744	8	0.913	0.993
F727	8	0.910	0.993
S730	8	0.910	0.997
F443	8	0.905	0.957
F467	8	0.895	0.958
H708	8	0.892	0.978
N530	8	0.869	0.962
N579	8	0.866	0.945
F483	8	0.851	0.957
D84	8	0.838	0.909
F418	8	0.835	0.949

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.51e-06

Disease associations

OMIM: gene MIM:603030 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
inflammatory bowel disease	Limited	Autosomal recessive

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
COVID-19 research	green

Mondo (1): inflammatory bowel disease (MONDO:0005265)

HPO phenotypes

showing 60 of 85 phenotypes (HPO-id order):

HPO	Term
HP:0000031	Epididymitis
HP:0000083	Renal insufficiency
HP:0000099	Glomerulonephritis
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000518	Cataract
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000708	Atypical behavior
HP:0000737	Irritability
HP:0001061	Acne
HP:0001097	Keratoconjunctivitis sicca
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001269	Hemiparesis
HP:0001287	Meningitis
HP:0001288	Gait disturbance
HP:0001289	Confusion
HP:0001347	Hyperreflexia
HP:0001369	Arthritis
HP:0001482	Subcutaneous nodule
HP:0001637	Abnormal myocardium morphology
HP:0001653	Mitral regurgitation
HP:0001658	Myocardial infarction
HP:0001659	Aortic regurgitation
HP:0001701	Pericarditis
HP:0001733	Pancreatitis
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001945	Fever
HP:0001954	Recurrent fever
HP:0002014	Diarrhea
HP:0002017	Nausea and vomiting
HP:0002024	Malabsorption
HP:0002027	Abdominal pain
HP:0002039	Anorexia
HP:0002076	Migraine
HP:0002102	Pleuritis
HP:0002105	Hemoptysis
HP:0002113	Pulmonary infiltrates
HP:0002202	Pleural effusion
HP:0002204	Pulmonary embolism
HP:0002239	Gastrointestinal hemorrhage
HP:0002315	Headache
HP:0002321	Vertigo
HP:0002354	Memory impairment
HP:0002376	Developmental regression
HP:0002383	Infectious encephalitis
HP:0002516	Increased intracranial pressure
HP:0002633	Vasculitis
HP:0002637	Cerebral ischemia
HP:0002638	Superficial thrombophlebitis
HP:0002716	Lymphadenopathy
HP:0002829	Arthralgia
HP:0003249	Genital ulcers
HP:0003326	Myalgia
HP:0003401	Paresthesia
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0004420	Arterial thrombosis
HP:0004936	Venous thrombosis

GWAS associations

showing 30 of 48 associations:

Study	Trait	p-value
GCST011494_75	Daytime nap	2e-13
GCST006940_87	Neurociticism	5e-12
GCST010989_28	Body size at age 10	5e-12
GCST005232_6	Neuroticism	1e-11
GCST002783_14	Body mass index	3e-11
GCST010988_71	Adult body size	2e-10
GCST002783_498	Body mass index	4e-10
GCST002783_153	Body mass index	8e-10
GCST004499_8	BMI in non-smokers	7e-9
GCST004495_25	BMI (adjusted for smoking behaviour)	1e-8
GCST004497_28	Body mass index (joint analysis main effects and smoking interaction)	1e-8
GCST004557_178	Body mass index	1e-8
GCST004557_196	Body mass index	1e-8
GCST005537_32	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	1e-8
GCST006944_12	Experiencing mood swings	1e-8
GCST004093_33	Prostate-specific antigen levels	2e-8
GCST004558_198	Body mass index (joint analysis main effects and physical activity interaction)	2e-8
GCST004558_6	Body mass index (joint analysis main effects and physical activity interaction)	2e-8
GCST006940_27	Neurociticism	2e-8
GCST006945_20	Feeling guilty	3e-8
GCST006947_32	Feeling fed-up	4e-8
GCST004559_173	Body mass index in physically active individuals	5e-8
GCST006941_34	Irritable mood	5e-8
GCST004559_65	Body mass index in physically active individuals	1e-7
GCST003075_138	Cognitive decline rate in late mild cognitive impairment	3e-7
GCST003075_10	Cognitive decline rate in late mild cognitive impairment	6e-7
GCST004495_26	BMI (adjusted for smoking behaviour)	7e-7
GCST003075_137	Cognitive decline rate in late mild cognitive impairment	8e-7
GCST004557_14	Body mass index	9e-7
GCST002444_4	Plasma omega-6 polyunsaturated fatty acid levels (dihomo-gamma-linolenic acid)	1e-6

EFO canonical traits (from GWAS)

22 canonical traits:

EFO ID	Trait name
EFO:0003940	physical activity
EFO:0005680	omega-6 polyunsaturated fatty acid measurement
EFO:0005890	osteoarthritis biomarker measurement
EFO:0004340	body mass index
EFO:0007710	cognitive decline measurement
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0007660	neuroticism measurement
EFO:0009594	irritability measurement
EFO:0008475	mood instability measurement
EFO:0009595	guilt measurement
EFO:0009588	feeling “fed-up” measurement
EFO:0006946	behavioural disinhibition measurement
EFO:0004346	neuroimaging measurement
EFO:0010543	uridine diphosphate galactose measurement
EFO:0010544	uridine diphosphate glucose measurement
EFO:0009769	histidine measurement
EFO:0010392	sphingomyelin 16:1 measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0007828	daytime rest measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D015212	Inflammatory Bowel Diseases	C06.405.205.731; C06.405.469.432

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL3038512 (PROTEIN COMPLEX), CHEMBL3038513 (PROTEIN COMPLEX), CHEMBL4106126 (PROTEIN-PROTEIN INTERACTION), CHEMBL5255 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the TLR4 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
RESATORVID	Small molecule	3

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes TLR4 — the drug acts on the assembly or class, not necessarily on this subunit alone.

1 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
ERITORAN TETRASODIUM	Toll-like receptor 4/MD-2	2	3

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 433,520 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

6 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL723	CARVEDILOL	4	30,479
CHEMBL34259	METHOTREXATE	4	402,177
CHEMBL5314354	POLYMYXIN B	4
CHEMBL225157	RESATORVID	3	436
CHEMBL501259	ERITORAN	3	375
CHEMBL3301672	ERITORAN TETRASODIUM	3	53

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

6 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs1927907	Other	3	tacrolimus	Organ Transplantation
rs2770150	Efficacy	3	Pertussis vaccines
rs4986790	Efficacy	3	pravastatin	Coronary Artery Disease
rs4986790	Toxicity	3	folic acid;methotrexate	Rheumatoid arthritis
rs4986790	Efficacy	3	Pertussis vaccines
rs5030728	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Inflammatory Bowel Diseases

PharmGKB variants

5 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1554973	CNPY4, TLR4	3	2.50	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs1927907	TLR4	3	2.25	1	tacrolimus
rs2770150	TLR4	3	2.50	1	Pertussis vaccines
rs4986790	TLR4	3	2.50	3	pravastatin;folic acid;methotrexate;Pertussis vaccines
rs5030728	TLR4	3	3.25	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

10 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1927907	tacrolimus	Metabolism/PK	Genotype CC is associated with increased concentrations of tacrolimus in people with liver transplantation as compared to genotypes CT + TT.	PMID:24820765
rs5030728	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Efficacy	Genotypes AA + AG is associated with increased response to Tumor necrosis factor alpha (TNF-alpha) inhibitors in people with Inflammatory Bowel Diseases as compared to genotype GG.	PMID:24776844
rs2770150	Pertussis vaccines	Efficacy	Genotype GG is associated with decreased response to Pertussis vaccines in children as compared to genotype AG.	PMID:17699831
rs4986790	Pertussis vaccines	Efficacy	Genotype AA is associated with increased response to Pertussis vaccines in children as compared to genotypes AG + GG.	PMID:22383676
rs1927911	acetaminophen	Toxicity	Genotypes AA + AG is associated with increased likelihood of Asthma when treated with acetaminophen in children as compared to genotype GG.	PMID:24851022
rs4986790	prednisolone	Efficacy	Allele G is associated with decreased clinical benefit to prednisolone in children with Thrombocytopenia as compared to allele A.	PMID:37638833
rs4986791	prednisolone	Efficacy	Allele T is associated with decreased clinical benefit to prednisolone in children with Thrombocytopenia as compared to allele C.	PMID:37638833
rs10759932	cisplatin	Toxicity	Allele C is associated with decreased likelihood of Ototoxicity when treated with cisplatin in children with Neoplasms as compared to allele T.	PMID:39488053
rs4986790	folic acid, methotrexate	Toxicity	Allele G is associated with increased risk of adverse drug events when treated with folic acid and methotrexate in people with Arthritis, Rheumatoid as compared to allele A.	PMID:20136356
rs4986790	pravastatin	Efficacy	Genotypes AG + GG are associated with decreased risk of cardiovascular events when treated with pravastatin in men with Coronary Artery Disease as compared to genotype AA.	PMID:12742999

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Toll-like receptor family

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
paridiprubart	Binding	9.86	pKd
GSK1795091	Agonist	9.77	pEC50

Binding affinities (BindingDB)

216 measured of 283 human assays (284 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL507938	EC50	0.01 nM
CHEMBL3354640	EC50	0.08 nM
CHEMBL5423611	EC50	0.11 nM
Preparation of N [(R)-3-Decyloxytetradecanoyl]-O-[2,3-di-[(R)-3-decyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-]-β-D-allopyranosyl]-L-serine	EC50	0.124 nM	US-10081622: Substituted indazole derivatives active as kinase inhibitors
CHEMBL5407900	EC50	0.13 nM
CHEMBL5407887	EC50	0.24 nM
Preparation of 2-[(R)-3-decanoyloxytetradecanoylamino]ethyl 2,3-di-[(R)-3-decanoyloxytetradecanoylamino]-2,3-dideoxy-4-O-phosphono-β-D-allopyranoside	EC50	0.251 nM	US-10081622: Substituted indazole derivatives active as kinase inhibitors
CHEMBL3354639	EC50	0.4 nM
[(3R)-1-[[(2R,4R,5S)-3-[[(3R)-3-decanoyloxytetradecanoyl]amino]-2-[(2S)-2-[[(3R)-3-decanoyloxytetradecanoyl]amino]-3-methoxy-3-oxopropoxy]-6-(hydroxymethyl)-5-phosphonooxyoxan-4-yl]amino]-1-oxotetradecan-3-yl] decanoate	EC50	0.462 nM	US-10081622: Substituted indazole derivatives active as kinase inhibitors
CHEMBL5417929	EC50	0.76 nM
CHEMBL5433813	EC50	1.2 nM
CHEMBL5428754	EC50	1.3 nM
E5564	IC50	1.5 nM
CHEMBL5432710	EC50	1.6 nM
(S)-2-((R)-3-(hexanoyloxy)tetradecanamido)-3-((2R,3R,4R,5S,6R)-3-((R)-3-(hexanoyloxy)tetradecanamido)-4-((R)-3-(hexanoyloxy)tetradecanoyloxy)-6-(hydroxymethyl)-5-(phosphonooxy)tetrahydro-2H-pyran-2-yloxy)propanoic acid	IC50	2.4 nM
CHEMBL4436411	KD	2.4 nM
(2S)-3-[(2R,4R,5S)-3,4-bis[[(3R)-3-decanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-sulfooxyoxan-2-yl]oxy-2-[[(3R)-3-decanoyloxytetradecanoyl]amino]propanoic acid	EC50	2.9 nM	US-10081622: Substituted indazole derivatives active as kinase inhibitors
[(2R,3S,4R,5R,6R)-6-[[(2R,3S,4R,5R,6S)-3,6-dihydroxy-5-[[(3R)-3-hydroxytetradecanoyl]amino]-4-[(3R)-3-hydroxytetradecanoyl]oxyoxan-2-yl]methoxy]-2-(hydroxymethyl)-5-[[(3R)-3-tetradecanoyloxytetradecanoyl]amino]-4-[(3R)-3-tetradecanoyloxytetradecanoyl]oxyoxan-3-yl] hydrogen phosphate	EC50	3.1 nM	US-10081622: Substituted indazole derivatives active as kinase inhibitors
ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate	IC50	3.2 nM
CHEMBL4463337	KD	4.9 nM
[(3R)-1-[2-[(2R,4R,5S)-6-(hydroxymethyl)-3,4-bis[[(3R)-3-(8-phenyloctanoyloxy)tetradecanoyl]amino]-5-phosphonooxyoxan-2-yl]oxyethylamino]-1-oxotetradecan-3-yl] 8-phenyloctanoate	EC50	4.99 nM	US-10081622: Substituted indazole derivatives active as kinase inhibitors
(S)-2-((R)-3-(hexyloxy)tetradecanamido)-3-((2R,3R,4R,5S,6R)-3-((R)-3-(hexyloxy)tetradecanamido)-4-((R)-3-(hexyloxy)tetradecanoyloxy)-6-(hydroxymethyl)-5-(phosphonooxy)tetrahydro-2H-pyran-2-yloxy)propanoic acid	IC50	5.3 nM
[(3R)-1-[2-[(2R,4R,5S)-3,4-bis[[(3R)-3-decanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-sulfooxyoxan-2-yl]oxyethylamino]-1-oxotetradecan-3-yl] decanoate	EC50	5.89 nM	US-10081622: Substituted indazole derivatives active as kinase inhibitors
[(3R)-1-[2-[(2R,4R,5S)-3-[[(3R)-3-decanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-4-[[(3R)-3-(8-phenyloctanoyloxy)tetradecanoyl]amino]-5-phosphonooxyoxan-2-yl]oxyethylamino]-1-oxotetradecan-3-yl] decanoate	EC50	15.7 nM	US-10081622: Substituted indazole derivatives active as kinase inhibitors
CHEMBL5174883	IC50	25 nM
CHEMBL3354641	EC50	31 nM
TAK-242	IC50	47 nM
VIZANTIN	IC50	53 nM
ethyl 5-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclopent-1-ene-1-carboxylate	IC50	110 nM
CHEMBL5422378	EC50	116 nM
CHEMBL5193233	IC50	150 nM
ethyl 6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate	IC50	160 nM
CHEMBL5084731	KD	180 nM
CHEMBL3360821	IC50	200 nM
CHEMBL5434803	EC50	200 nM
7-(2-Chloro-4-fluoro-phenylsulfamoyl)-cyclohept-1-enecarboxylic acid ethyl ester	IC50	240 nM
CHEMBL4643502	IC50	250 nM
CHEMBL5186900	IC50	350 nM
CHEMBL6152217	IC50	354 nM
CHEMBL3261034	EC50	390 nM
CHEMBL6145104	IC50	415 nM
CHEMBL4068003	EC50	430 nM
CHEMBL5422246	IC50	430 nM
CHEMBL3261029	EC50	500 nM
CHEMBL5202822	IC50	520 nM
CHEMBL4875156	IC50	560 nM
CHEMBL5076109	KD	570 nM
CHEMBL6160868	IC50	611 nM
CHEMBL3261031	EC50	630 nM
CHEMBL3261032	EC50	630 nM

ChEMBL bioactivities

234 potent at pChembl≥5 of 286 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	EC50	0.01	nM	CHEMBL507938
10.85	EC50	0.014	nM	CHEMBL507938
10.55	EC50	0.028	nM	CHEMBL507938
10.22	EC50	0.06	nM	CHEMBL507938
10.10	EC50	0.08	nM	CHEMBL3354640
9.96	EC50	0.11	nM	CHEMBL5423611
9.89	EC50	0.13	nM	CHEMBL5407900
9.89	EC50	0.13	nM	CHEMBL5423611
9.85	EC50	0.14	nM	CHEMBL5407900
9.77	ED50	0.17	nM	CHEMBL507938
9.70	EC50	0.2	nM	CHEMBL5423611
9.62	EC50	0.24	nM	CHEMBL5407887
9.59	EC50	0.26	nM	CHEMBL5423611
9.59	EC50	0.26	nM	CHEMBL507938
9.55	EC50	0.28	nM	CHEMBL5407900
9.42	EC50	0.38	nM	CHEMBL5407900
9.41	ED50	0.39	nM	CHEMBL448191
9.40	EC50	0.4	nM	CHEMBL3354639
9.34	EC50	0.46	nM	CHEMBL5407887
9.19	EC50	0.65	nM	CHEMBL5407887
9.12	EC50	0.76	nM	CHEMBL5417929
9.03	EC50	0.93	nM	CHEMBL507938
9.01	EC50	0.97	nM	CHEMBL5407887
9.00	EC50	0.99	nM	CHEMBL5417929
8.91	EC50	1.23	nM	CHEMBL5433813
8.90	EC50	1.26	nM	CHEMBL5428754
8.88	EC50	1.33	nM	CHEMBL5423611
8.83	EC50	1.49	nM	CHEMBL5433813
8.82	IC50	1.5	nM	ERITORAN
8.82	IC50	1.5	nM	ERITORAN TETRASODIUM
8.79	EC50	1.61	nM	CHEMBL5432710
8.78	EC50	1.65	nM	CHEMBL5432710
8.75	EC50	1.78	nM	CHEMBL5433813
8.72	EC50	1.92	nM	CHEMBL5417929
8.71	EC50	1.94	nM	CHEMBL5428754
8.68	EC50	2.11	nM	CHEMBL5417929
8.62	IC50	2.4	nM	CHEMBL505526
8.59	EC50	2.6	nM	CHEMBL5407900
8.58	EC50	2.62	nM	CHEMBL5428754
8.57	EC50	2.69	nM	CHEMBL5433813
8.54	EC50	2.87	nM	CHEMBL5422378
8.49	IC50	3.2	nM	CHEMBL426184
8.43	EC50	3.68	nM	CHEMBL5432710
8.32	IC50	4.75	nM	CHEMBL5174883
8.28	IC50	5.3	nM	CHEMBL501231
8.21	EC50	6.23	nM	CHEMBL5417929
8.20	EC50	6.37	nM	CHEMBL5434803
8.17	EC50	6.75	nM	CHEMBL5428754
8.16	EC50	6.88	nM	CHEMBL5407887
8.15	EC50	7.01	nM	CHEMBL5422378

PubChem BioAssay actives

231 with measured affinity, of 1227 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(3R)-3-decoxytetradecanoyl]amino]-3-[(2R,3R,4R,5S,6R)-3-[[(3R)-3-decoxytetradecanoyl]amino]-4-[(3R)-3-decoxytetradecanoyl]oxy-6-(hydroxymethyl)-5-phosphonooxyoxan-2-yl]oxypropanoic acid	2020049: Agonist activity at TLR4 in human PBMC cells assessed as induction of MIP-1beta release incubated for 20 hrs by ELISA	ec50	<0.0001	uM
[(2R,3S,4S,5S,6R)-6-[(2R,3R,4R,5S,6R)-3-[[(3R)-3-dodecanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-phosphonooxy-4-[(3R)-3-tetradecanoyloxytetradecanoyl]oxyoxan-2-yl]oxy-4-hydroxy-5-methoxy-2-(phosphonooxymethyl)oxan-3-yl] (3S)-3-decanoyloxytetradecanoate	1166076: Agonist activity at human TLR4 expressed in HEK293 cells coexpressed with human MD2/CD14 assessed as activation of NFkappaB signaling after 20 to 24 hrs by NFkappaB reporter assay	ec50	0.0001	uM
(2S)-3-[(2R,3R,4S,5S,6R)-3,4-bis[[(3R)-3-decoxytetradecanoyl]amino]-6-(hydroxymethyl)-5-phosphonooxyoxan-2-yl]oxy-2-[[(3R)-3-decoxytetradecanoyl]amino]propanoic acid;N,N-diethylethanamine	2020049: Agonist activity at TLR4 in human PBMC cells assessed as induction of MIP-1beta release incubated for 20 hrs by ELISA	ec50	0.0001	uM
(2S)-3-[(2R,3R,4R,5R,6S)-3,4-bis[[(3R)-3-decoxytetradecanoyl]amino]-6-(hydroxymethyl)-5-(phosphonooxymethyl)oxan-2-yl]oxy-2-[[(3R)-3-decoxytetradecanoyl]amino]propanoic acid;N,N-diethylethanamine	2020049: Agonist activity at TLR4 in human PBMC cells assessed as induction of MIP-1beta release incubated for 20 hrs by ELISA	ec50	0.0001	uM
(2S)-3-[(2R,3R,4S,5S,6R)-3,4-bis[[(3R)-3-decoxytetradecanoyl]amino]-6-(hydroxymethyl)-5-sulfooxyoxan-2-yl]oxy-2-[[(3R)-3-decoxytetradecanoyl]amino]propanoic acid;N,N-diethylethanamine	2020049: Agonist activity at TLR4 in human PBMC cells assessed as induction of MIP-1beta release incubated for 20 hrs by ELISA	ec50	0.0002	uM
[(2R,3S,4S,5S,6R)-6-[(2R,3R,4R,5S,6R)-3-[[(3R)-3-dodecanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-phosphonooxy-4-[(3R)-3-tetradecanoyloxytetradecanoyl]oxyoxan-2-yl]oxy-4-hydroxy-5-methoxy-2-(phosphonooxymethyl)oxan-3-yl] (3S)-3-dodecanoyloxytetradecanoate	1166076: Agonist activity at human TLR4 expressed in HEK293 cells coexpressed with human MD2/CD14 assessed as activation of NFkappaB signaling after 20 to 24 hrs by NFkappaB reporter assay	ec50	0.0004	uM
[(2S,3R,4R,5S,6R)-2,5-dihydroxy-6-[[(2R,3R,4R,5S,6R)-6-(hydroxymethyl)-5-phosphonooxy-3-[[(3S)-3-tetradecanoyloxytetradecanoyl]amino]-4-[(3R)-3-tetradecanoyloxytetradecanoyl]oxyoxan-2-yl]oxymethyl]-3-[[(3R)-3-hydroxytetradecanoyl]amino]oxan-4-yl] (3R)-3-hydroxytetradecanoate	2020049: Agonist activity at TLR4 in human PBMC cells assessed as induction of MIP-1beta release incubated for 20 hrs by ELISA	ec50	0.0008	uM
[(3R)-1-[2-[(2R,3R,4R,5R,6S)-3,4-bis[[(3R)-3-decanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-(phosphonooxymethyl)oxan-2-yl]oxyethylamino]-1-oxotetradecan-3-yl] decanoate;N,N-diethylethanamine	2020049: Agonist activity at TLR4 in human PBMC cells assessed as induction of MIP-1beta release incubated for 20 hrs by ELISA	ec50	0.0012	uM
[(2R,3R,4R,5S,6R)-3-[[(3R)-3-decanoyloxytetradecanoyl]amino]-2-[2-[[(3R)-3-decanoyloxytetradecanoyl]amino]ethoxy]-6-(hydroxymethyl)-5-phosphonooxyoxan-4-yl] (3R)-3-decanoyloxytetradecanoate	2020052: Agonist activity at TLR4 in human PBMC cells assessed as induction of RANTES release incubated for 20 hrs by ELISA	ec50	0.0013	uM
tetrasodium;[(2R,3R,4R,5S,6R)-4-decoxy-5-hydroxy-6-[[(2R,3R,4R,5S,6R)-4-[(3R)-3-methoxydecoxy]-6-(methoxymethyl)-3-[[(Z)-octadec-11-enoyl]amino]-5-phosphonatooxyoxan-2-yl]oxymethyl]-3-(3-oxotetradecanoylamino)oxan-2-yl] phosphate	389407: Antagonist activity at human TLR4 expressed in HE293 cells by ELAM1-luciferase reporter gene assay	ic50	0.0015	uM
[(2R,3R,4R,5S,6R)-4-decoxy-5-hydroxy-6-[[(2R,3R,4R,5S,6R)-4-[(3R)-3-methoxydecoxy]-6-(methoxymethyl)-3-[[(Z)-octadec-11-enoyl]amino]-5-phosphonooxyoxan-2-yl]oxymethyl]-3-(3-oxotetradecanoylamino)oxan-2-yl] dihydrogen phosphate	1525540: Antagonist activity at TLR4 in human serum assessed as reduction in LPS-induced TNFalpha production after 3 hrs by ELISA	ic50	0.0015	uM
[(3R)-1-[2-[(2R,3R,4S,5S,6R)-3,4-bis[[(3R)-3-decanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-phosphonooxyoxan-2-yl]oxyethylamino]-1-oxotetradecan-3-yl] decanoate;N,N-diethylethanamine	2020048: Agonist activity at TLR4 in human MONO-MAC-6 cells assessed as induction of MIP-1beta release incubated for 24 hrs by ELISA	ec50	0.0016	uM
(2S)-2-[[(3R)-3-hexanoyloxytetradecanoyl]amino]-3-[(2R,3R,4R,5S,6R)-3-[[(3R)-3-hexanoyloxytetradecanoyl]amino]-4-[(3R)-3-hexanoyloxytetradecanoyl]oxy-6-(hydroxymethyl)-5-phosphonooxyoxan-2-yl]oxypropanoic acid	344746: Antagonist activity at TLR4 in human PBMC assessed as inhibition of LPS-stimulated TNFalpha production pre-incubated for 30 mins before LPS challenge measured after 18 hrs by ELISA	ic50	0.0024	uM
[(3R)-1-[2-[(2R,3R,4S,5S,6R)-3,4-bis[[(3R)-3-decanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-sulfooxyoxan-2-yl]oxyethylamino]-1-oxotetradecan-3-yl] decanoate;N,N-diethylethanamine	2020049: Agonist activity at TLR4 in human PBMC cells assessed as induction of MIP-1beta release incubated for 20 hrs by ELISA	ec50	0.0029	uM
ethyl 6-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate	389410: Inhibition of human TLR4-mediated cytokine production in mouse macrophages	ic50	0.0032	uM
methyl (1R,4aS,6S,7R,7aS)-1,6-dihydroxy-7-methyl-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-4-carboxylate	1872823: Antagonist activity at human TLR4 expressed in HEK-blue hTLR4/MD2-CE14 cells cotransfected with pISRE-TA plasmid assessed as reduction in ISRE activation incubated for overnight by dual-Glo luciferase assay	ic50	0.0047	uM
(2S)-2-[[(3R)-3-hexoxytetradecanoyl]amino]-3-[(2R,3R,4R,5S,6R)-3-[[(3R)-3-hexoxytetradecanoyl]amino]-4-[(3R)-3-hexoxytetradecanoyl]oxy-6-(hydroxymethyl)-5-phosphonooxyoxan-2-yl]oxypropanoic acid	344746: Antagonist activity at TLR4 in human PBMC assessed as inhibition of LPS-stimulated TNFalpha production pre-incubated for 30 mins before LPS challenge measured after 18 hrs by ELISA	ic50	0.0053	uM
[(3R)-1-[[(2S,3R,4R,5S,6R)-6-[[(2R,3R,4R,5S,6R)-3-[[(3R)-3-dodecanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-phosphonooxy-4-[(3R)-3-tetradecanoyloxytetradecanoyl]oxyoxan-2-yl]oxymethyl]-2,4,5-trihydroxyoxan-3-yl]amino]-1-oxotetradecan-3-yl] hexadecanoate	2020048: Agonist activity at TLR4 in human MONO-MAC-6 cells assessed as induction of MIP-1beta release incubated for 24 hrs by ELISA	ec50	0.0064	uM
[(2R,3S,4S,5S,6R)-6-[(2R,3R,4R,5S,6R)-3-[[(3R)-3-dodecanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-phosphonooxy-4-[(3R)-3-tetradecanoyloxytetradecanoyl]oxyoxan-2-yl]oxy-4-hydroxy-2-(hydroxymethyl)-5-methoxyoxan-3-yl] (3S)-3-dodecanoyloxytetradecanoate	1166076: Agonist activity at human TLR4 expressed in HEK293 cells coexpressed with human MD2/CD14 assessed as activation of NFkappaB signaling after 20 to 24 hrs by NFkappaB reporter assay	ec50	0.0310	uM
ethyl (6R)-6-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate	2223285: Inhibition of human TLR4 in LPS-stimulated HEK-Blue hTLR4 cells assessed as reduction in SEAP activity incubated for 24 hrs by microplate reader assay	ic50	0.0470	uM
[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(3-nonyldodecanoyloxymethyl)oxan-2-yl]oxyoxan-2-yl]methyl 3-nonyldodecanoate	1989275: Inhibition of TLR4 in human HEK293T cells co-expressing MD-2 receptor	ic50	0.0530	uM
3-[2-[[(2S)-3-[(3S)-3-dodecanoyloxydecoxy]-2-(tetradecanoylamino)propoxy]-hydroxyphosphoryl]oxyethylamino]-2-[(4-hydroxyphenyl)methyl]-3-oxopropanoic acid	257620: Antagonistic potency at human TLR4 expressed in HEK293 cells	ic50	0.0800	uM
ethyl 5-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclopentene-1-carboxylate	389410: Inhibition of human TLR4-mediated cytokine production in mouse macrophages	ic50	0.1100	uM
N-[(2S,3R,4R,5S,6R)-2-[(2R,3S,4R,5R,6S)-5-acetamido-6-[(2R,3S,4R,5R,6S)-5-acetamido-6-[(2R,3S,4R,5R,6S)-5-acetamido-6-[(2R,3S,4R,5R,6S)-5-acetamido-6-[(2R,3S,4R,5R,6R)-5-acetamido-6-cyclohexyloxy-4-hydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-4-hydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-4-hydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-4-hydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-4-hydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide	1872819: Binding affinity to TLR4 in human THP-1 monocytes after 48 hrs by ELISA	ic50	0.1500	uM
3-[2-[[(2R)-3-[(3S)-3-dodecanoyloxydecoxy]-2-(tetradecanoylamino)propoxy]-hydroxyphosphoryl]oxyethylamino]-2-[(4-hydroxyphenyl)methyl]-3-oxopropanoic acid	257620: Antagonistic potency at human TLR4 expressed in HEK293 cells	ic50	0.1600	uM
ethyl 6-[(4-chloro-2-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate	389410: Inhibition of human TLR4-mediated cytokine production in mouse macrophages	ic50	0.1600	uM
disodium;[(2R,3R,4R,5S,6R)-6-(hydroxymethyl)-3-(tetradecanoylamino)-4,5-di(tetradecanoyloxy)oxan-2-yl] phosphate	1809155: Binding affinity to NTA sensor chip immobilized recombinant human TLR4/MD2 assessed as dissociation constant by surface plasmon resonance analysis	kd	0.1800	uM
[(2R,3R,4S,5S,6R)-2-[[4-[[bis(2-aminoethyl)amino]methyl]triazol-1-yl]methyl]-6-[(2R,3R,4S,5R,6R)-6-[[4-[[bis(2-aminoethyl)amino]methyl]triazol-1-yl]methyl]-3,4,5-tri(hexanoyloxy)oxan-2-yl]oxy-4,5-di(hexanoyloxy)oxan-3-yl] hexanoate;hydrochloride	1166984: Antagonist activity at human TLR4 expressed in HEK293 cells co-transfected with human MD-2/CD14 assessed as inhibition of LPS-stimulated receptor signal after 2 to 4 hrs by dual luciferase reporter gene assay	ic50	0.2000	uM
2-[4-[[5,11,17,23-tetratert-butyl-26,27,28-tris[4-(diaminomethylideneamino)butoxy]-25-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(24),3,5,7(28),9,11,13(27),15(26),16,18,21(25),22-dodecaenyl]oxy]butyl]guanidine;tetrahydrochloride	1447912: Binding affinity to CD14/MD2 (unknown origin) expressed in HEK-Blue cells co-expressing TLR4 assessed as inhibition of LPS-induced TLR4 signaling preincubated for 30 mins followed by LPS stimulation measured after overnight incubation by secreted embryonic alkaline phosphatase reporter gene assay	ic50	0.2000	uM
ethyl 7-[(2-chloro-4-fluorophenyl)sulfamoyl]cycloheptene-1-carboxylate	389410: Inhibition of human TLR4-mediated cytokine production in mouse macrophages	ic50	0.2400	uM
1,3-dimethyl-5-(7-methyl-2-piperidin-4-ylindazol-5-yl)pyridin-2-one	1661553: Antagonist activity at TLR4 in human PBMC assessed as inhibition of LPS-induced TNFalpha production preincubated for 30 mins followed by LPS addition and measured after 20 hrs by HTRF assay	ic50	0.2500	uM
3-[2-[[(2S)-3-[(3R)-3-dodecanoyloxydecoxy]-2-(tetradecanoylamino)propoxy]-hydroxyphosphoryl]oxyethylamino]-2-[(4-hydroxyphenyl)methyl]-3-oxopropanoic acid	257620: Antagonistic potency at human TLR4 expressed in HEK293 cells	ic50	0.2500	uM
2-[3-[(E)-2-nitroethenyl]phenyl]pyridine	1853314: Antagonist activity at human TLR4 in HEK-Blue hTLR4 cells assessed as inhibition of LPS-induced receptor activation preincubated with LPS followed by compound addition and measured 24 hrs by Quanti-Blue based SEAP reporter gene assay	ic50	0.2800	uM
ethyl 6-[(2-chloro-4-fluorophenyl)-prop-2-ynylsulfamoyl]cyclohexene-1-carboxylate	1578541: Inhibition of human TLR4 expressed in HEK-Blue cells assessed as decrease in LPS-induced TLR4 response incubated for 1 hr followed by LPS stimulation and further incubated for 22 hrs by cell based reporter assay	ic50	0.3340	uM
3-[2-[[(2R)-3-[(3R)-3-dodecanoyloxydecoxy]-2-(tetradecanoylamino)propoxy]-hydroxyphosphoryl]oxyethylamino]-2-[(4-hydroxyphenyl)methyl]-3-oxopropanoic acid	257620: Antagonistic potency at human TLR4 expressed in HEK293 cells	ic50	0.3500	uM
[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-[5-(4-chlorophenyl)-7-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanone	2223285: Inhibition of human TLR4 in LPS-stimulated HEK-Blue hTLR4 cells assessed as reduction in SEAP activity incubated for 24 hrs by microplate reader assay	ic50	0.3540	uM
(11R,12R,13R,14S)-13-cyclopentyl-12-(3,4-dimethoxyphenyl)-15,15-dimethyl-16-oxa-8-azatetracyclo[8.6.0.02,7.011,14]hexadeca-1(10),2,4,6-tetraen-9-one	1138177: Agonist activity at human recombinant TLR4 expressed in HEK293 cells by SEAP reporter assay	ec50	0.3900	uM
(5-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-[5-(4-chlorophenyl)-7-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanone	2223285: Inhibition of human TLR4 in LPS-stimulated HEK-Blue hTLR4 cells assessed as reduction in SEAP activity incubated for 24 hrs by microplate reader assay	ic50	0.4150	uM
N-cyclohexyl-2-(5-methyl-4-oxo-3,8-diphenylpyrimido[5,4-b]indol-2-yl)sulfanylacetamide	1476760: Agonist activity at human TLR4 expressed in HEK293 blue cells assessed as induction of NF-kappaB activation-mediated SEAP production after 20 to 24 hrs by colorimetric assay	ec50	0.4300	uM
1-(5-hydroxy-2-oxocyclohexyl)butane-1,3-dione	2004680: Inhibition of TLR4 (unknown origin) using TMB as substrate incubated for 90 mins	ic50	0.4300	uM
N-[3-[(E)-2-nitroethenyl]phenyl]pyridin-2-amine	1853314: Antagonist activity at human TLR4 in HEK-Blue hTLR4 cells assessed as inhibition of LPS-induced receptor activation preincubated with LPS followed by compound addition and measured 24 hrs by Quanti-Blue based SEAP reporter gene assay	ic50	0.4600	uM
(11R,12R,13R,14S)-12-[3-(2-hydroxyethoxy)-4-methoxyphenyl]-15,15-dimethyl-13-propan-2-yl-16-oxa-8-azatetracyclo[8.6.0.02,7.011,14]hexadeca-1(10),2,4,6-tetraen-9-one	1138177: Agonist activity at human recombinant TLR4 expressed in HEK293 cells by SEAP reporter assay	ec50	0.5000	uM
(NE)-N-[1-(6-methoxy-1,3-benzoxazol-2-yl)-2-(4-methoxyphenyl)ethylidene]hydroxylamine	1389561: Inhibition of human TLR4 signaling expressed in HEK-Blue cells co-expressing MD2/CD14 assessed as reduction in LPS-induced NF-kappaB activation-mediated SEAP production preincubated for 2 hrs followed by LPS stimulation for 20 hrs by colorimetric assay	ic50	0.5400	uM
benzyl N-[(2R)-6,8-dioxo-2,3,4,8a-tetrahydro-1H-naphthalen-2-yl]carbamate	1768717: Inhibition of TLR4 (unknown origin) by sandwich ELISA method	ic50	0.5600	uM
disodium;[(2R,3R,4R,5S,6R)-3-(dodecanoylamino)-4,5-di(dodecanoyloxy)-6-(hydroxymethyl)oxan-2-yl] phosphate	1809155: Binding affinity to NTA sensor chip immobilized recombinant human TLR4/MD2 assessed as dissociation constant by surface plasmon resonance analysis	kd	0.5700	uM
[(2R,3R,4S,5S,6R)-2-[[4-[(2-aminoethylcarbamothioylamino)methyl]triazol-1-yl]methyl]-6-[(2R,3R,4S,5R,6R)-6-[[4-[(2-aminoethylcarbamothioylamino)methyl]triazol-1-yl]methyl]-3,4,5-tri(hexanoyloxy)oxan-2-yl]oxy-4,5-di(hexanoyloxy)oxan-3-yl] hexanoate;hydrochloride	1166984: Antagonist activity at human TLR4 expressed in HEK293 cells co-transfected with human MD-2/CD14 assessed as inhibition of LPS-stimulated receptor signal after 2 to 4 hrs by dual luciferase reporter gene assay	ic50	0.6000	uM
[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-[5-(3,4-dichlorophenyl)-7-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanone	2223285: Inhibition of human TLR4 in LPS-stimulated HEK-Blue hTLR4 cells assessed as reduction in SEAP activity incubated for 24 hrs by microplate reader assay	ic50	0.6110	uM
disodium;[(2R,3R,4R,5S,6R)-3-(dodecanoylamino)-4-dodecanoyloxy-6-(hydroxymethyl)-5-[hydroxy(oxido)phosphoryl]oxyoxan-2-yl] hydrogen phosphate	1455595: Antagonist activity at human TLR4 expressed in HEK blue cells assessed as inhibition of LPS-induced NF-kappaB activation-mediated SEAP production preincubated for 30 mins followed by LPS addition measured after overnight incubation in absence of light by NF-kappaB reporter gene assay	ic50	0.6300	uM
(11R,12R,13R,14S)-13-cyclopropyl-12-(3,4-dimethoxyphenyl)-15,15-dimethyl-16-oxa-8-azatetracyclo[8.6.0.02,7.011,14]hexadeca-1(10),2,4,6-tetraen-9-one	1138177: Agonist activity at human recombinant TLR4 expressed in HEK293 cells by SEAP reporter assay	ec50	0.6300	uM
(11R,12R,13R,14S)-13-cyclopropyl-15,15-dimethyl-12-(3,4,5-trimethoxyphenyl)-16-oxa-8-azatetracyclo[8.6.0.02,7.011,14]hexadeca-1(10),2,4,6-tetraen-9-one	1138177: Agonist activity at human recombinant TLR4 expressed in HEK293 cells by SEAP reporter assay	ec50	0.6300	uM

CTD chemical–gene interactions

230 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects cotreatment, affects reaction, affects binding, increases activity, increases cleavage (+12 more)	49
Tobacco Smoke Pollution	decreases reaction, increases expression, decreases expression	12
lipopolysaccharide, Escherichia coli O111 B4	decreases reaction, increases expression, increases reaction, affects reaction, affects cotreatment (+1 more)	8
ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate	decreases activity, decreases expression, affects reaction, decreases reaction, increases expression (+1 more)	8
lipopolysaccharide, E coli O55-B5	increases activity, increases secretion, increases reaction, affects reaction, decreases reaction (+3 more)	7
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases expression, decreases reaction	6
Particulate Matter	increases abundance, increases expression, decreases reaction, affects expression, decreases expression	6
Resveratrol	affects cotreatment, decreases secretion, increases secretion, decreases reaction, increases expression (+6 more)	5
Quercetin	increases reaction, affects expression, affects cotreatment, decreases reaction, increases expression (+1 more)	5
Cadmium	decreases expression, increases expression, decreases reaction	4
Ozone	increases abundance, increases expression, affects expression, affects cotreatment, decreases expression	4
Paraquat	decreases reaction, increases expression, affects reaction	4
Progesterone	affects cotreatment, decreases reaction, increases expression	4
Valproic Acid	decreases expression, decreases methylation, increases expression	4
Cadmium Chloride	increases expression, increases reaction, increases phosphorylation	4
bisphenol A	affects binding, increases expression, increases reaction	3
nuciferine	decreases reaction, increases expression, decreases expression	3
sodium arsenite	increases abundance, increases expression, decreases expression	3
nickel chloride	decreases reaction, increases expression, affects binding, increases activity, affects reaction (+1 more)	3
lipopolysaccharide, E. coli O26-B6	affects reaction, increases expression, affects localization, increases reaction, decreases expression	3
Arsenic	increases expression, increases abundance	3
Smoke	decreases expression, increases expression	3
Tetradecanoylphorbol Acetate	affects cotreatment, decreases reaction, increases expression, affects reaction, increases secretion	3
1-(3,4-dihydroxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one	decreases reaction, increases reaction, affects binding	2
sulforaphane	increases expression	2
cobaltous chloride	affects binding, increases activity, affects reaction, increases secretion	2
epigallocatechin gallate	affects cotreatment, decreases reaction, increases expression	2
(+)-JQ1 compound	decreases expression, affects cotreatment	2
Atorvastatin	increases expression, affects cotreatment, decreases expression	2
Microplastics	increases abundance, increases expression, affects reaction, increases secretion	2

ChEMBL screening assays

267 unique, capped per target: 254 binding, 10 functional, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2378352	Binding	Agonist activity at TLR4/MD-2 receptor complex in human THP1 cells assessed as IL-1beta release at 0.001 uM after 24 hrs by ELISA in presence of lipid IVa in presence of 0.1 uM of lipid IVa	Improving the immunostimulatory potency of diethanolamine-containing lipid A mimics. — *Bioorg Med Chem*
CHEMBL3373551	ADMET	Activation of TLR4/MD2 (unknown origin) expressed in HEK293 cells co-expressing CD14 assessed as induction of MyD88-dependent NF-kappaB activity after 24 hrs by NF-kappaB SEAP reporter gene assay	Characterization of TRIF selectivity in the AGP class of lipid A mimetics: role of secondary lipid chains. — *Bioorg Med Chem Lett*
CHEMBL1913436	Functional	Partial agonist activity at TLR4 transfected in Sf9 insect cells assessed as inhibition of LPS-mediated sTLR4/MD2 homodimerization after 1 hr by native PAGE	Synthesis and Toll-like receptor 4 (TLR4) activity of phosphatidylinositol dimannoside analogues. — *J Med Chem*

Cellosaurus cell lines

27 cell lines: 15 cancer cell line, 11 transformed cell line, 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5L02	JS2 TLR4-/- WT	Transformed cell line	Sex unspecified
CVCL_5L03	JS2 TLR4-/- D299G	Transformed cell line	Sex unspecified
CVCL_5L04	JS2 TLR4-/- T399I	Transformed cell line	Sex unspecified
CVCL_5L05	JS2 TLR4-/- D299G/T399I	Transformed cell line	Sex unspecified
CVCL_A8AX	THP1-Dual KO-TLR4	Cancer cell line	Male
CVCL_B5KZ	HAP1 TLR4 (-) 2	Cancer cell line	Male
CVCL_B5L0	HAP1 TLR4 (-) 3	Cancer cell line	Male
CVCL_B8QZ	Abcam HCT 116 TLR4 KO	Cancer cell line	Male
CVCL_B9TD	Abcam A-549 TLR4 KO	Cancer cell line	Male
CVCL_C9JB	WAe009-A-N	Embryonic stem cell	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 598 trials:

NCT	Phase	Status	Title
NCT00167882	Phase 4	COMPLETED	The Influence of 5-Aminosalicylates on Thiopurine Metabolite Levels
NCT00205062	Phase 4	TERMINATED	Positron Emission Tomography (PET)-Computed Tomography (CT) in Inflammatory Bowel Disease (IBD)
NCT00567593	Phase 4	COMPLETED	Gene Regulation by Thiazolidinediones
NCT00746395	Phase 4	COMPLETED	Randomized, Placebo-controlled Trial of Lubiprostone as a Preparation for Capsule Endoscopy
NCT01034358	Phase 4	COMPLETED	Immune Response to the Human Papillomavirus Vaccine in Young Women With Inflammatory Bowel Disease
NCT01056913	Phase 4	COMPLETED	NITI CAR27 (ColonRing) Compression Anastomosis in Colorectal Surgery
NCT01067547	Phase 4	COMPLETED	A Trial of Iron Replacement in Patients With Iron Deficiency.
NCT01341808	Phase 4	COMPLETED	Immunogenicity of Hepatitis A Vaccine in Inflammatory Bowel Disease (IBD) Patients
NCT01908283	Phase 4	COMPLETED	Induction of Immunity Against Streptococcus Pneumoniae in Adults With Inflammatory Bowel Disease
NCT01934088	Phase 4	COMPLETED	Satisfaction With Nurse Administered Propofol Sedation vs. Midazolam With Fentanyl Sedation for Endoscopy
NCT02162862	Phase 4	COMPLETED	Treating Disrupted Sleep in Individuals With Inflammatory Bowel Disease
NCT02248337	Phase 4	COMPLETED	Low Volume Colon Preparation for IBD
NCT02281799	Phase 4	WITHDRAWN	Thiopurine Induced Pancreatitis in IBD Patients
NCT02392286	Phase 4	TERMINATED	Corticosteroid Dosage for Crohn’s Disease Flare
NCT02437591	Phase 4	COMPLETED	Study to Evaluate the Pharmacokinetics of Fidaxomicin in Inflammatory Bowel Disease (IBD) Subjects With Clostridium Difficile Infection (CDI)
NCT02453776	Phase 4	COMPLETED	Precision Dosing of Infliximab Versus Conventional Dosing of Infliximab
NCT02461758	Phase 4	COMPLETED	Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory Bowel Disease Patients
NCT02566889	Phase 4	TERMINATED	An Efficacy and Safety Study of Infliximab Dose Escalation in Pediatric Participants With Inflammatory Bowel Disease
NCT02774057	Phase 4	UNKNOWN	Trial of Captafer® vs. Oral Iron Sulfate in the Treatment of Iron Deficiency Anemia in Patients With IBD
NCT02806206	Phase 4	UNKNOWN	Prucalopride Prior to Small Bowel Capsule Endoscopy
NCT02946203	Phase 4	COMPLETED	Comparison of VoLumen and Breeza Oral Contrast Agents in Pediatric Patients
NCT02994836	Phase 4	COMPLETED	GIS-SUSANTI-TNF-2015 (Anti-TNF Discontinuation )
NCT03220841	Phase 4	UNKNOWN	Stricture Definition and Treatment (STRIDENT) Drug Therapy Study
NCT03351972	Phase 4	COMPLETED	Differences in Preparation for Small Bowel Capsule Endoscopy
NCT03466983	Phase 4	COMPLETED	A Trial Comparing the Incidence of Hypophosphatemia in Relation to Treatment With Iron Isomaltoside and Ferric Carboxymaltose in Subjects With Iron Deficiency Anaemia Due to Inflammatory Bowel Disease
NCT03591770	Phase 4	TERMINATED	Shingrix Vaccine in Patients With Moderate to Severe Ulcerative Colitis on Tofacitinib
NCT03629379	Phase 4	COMPLETED	Response to Ustekinumab for Anti-tnf Induced Psoriasiform Skin Lesions
NCT03723447	Phase 4	COMPLETED	Intraoperative TAP Block With Bupivacaine/Dexamethasone Against Liposomal Bupivacaine (Exparel®)
NCT03798691	Phase 4	COMPLETED	Immunogenicity of Herpes Zoster Subunit Vaccine in Inflammatory Bowel Disease Patients Treated With Vedolizumab
NCT03860012	Phase 4	UNKNOWN	Folic Acid in Pediatric Inflammatory Bowel Disease
NCT03885713	Phase 4	COMPLETED	Identification of Predictive Biomarkers for Response to Biologic Therapies and Tofacitinib in Inflammatory Bowel Disease
NCT03917303	Phase 4	RECRUITING	Control Crohn Safe Trial
NCT04045782	Phase 4	COMPLETED	Evaluation of the Safety and Effectiveness of Switching From Humira® to Imraldi® in Flanders
NCT04304950	Phase 4	COMPLETED	Chronotherapy in Inflammatory Bowel Disease
NCT04626947	Phase 4	TERMINATED	Prevention of Recurrent Clostridium Difficile Infection (CDI) in Patients With Inflammatory Bowel Disease (IBD).
NCT04646187	Phase 4	ENROLLING_BY_INVITATION	De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
NCT04835506	Phase 4	ACTIVE_NOT_RECRUITING	Proactive Infliximab Optimization Using a Pharmacokinetic Dashboard Versus Standard of Care in Patients With Inflammatory Bowel Disease: The OPTIMIZE Trial
NCT04982172	Phase 4	COMPLETED	Model-informed Dose De-escalation of Infliximab in Patients With Inflammatory Bowel Diseases
NCT05180175	Phase 4	COMPLETED	The Nordic IBD Treatment Strategy Trial
NCT05280405	Phase 4	UNKNOWN	Early Proactive Therapeutic Drug Monitoring of Infliximab in Children: EPIC Study
NCT05340764	Phase 4	COMPLETED	Safety of Reduced Infliximab Infusion Time
NCT05439772	Phase 4	COMPLETED	Examining the Effect of Ondansetron on Bowel Prep Success
NCT05456932	Phase 4	UNKNOWN	Predicting Response to Iron Supplementation in Patients With Active Inflammatory Bowel Disease
NCT06055543	Phase 4	UNKNOWN	Impact of a New Plant-based High-energy Oral Nutritional Supplement on Nutritional Outcomes in Malnourished Patients
NCT06113913	Phase 4	RECRUITING	Subcutaneous Infliximab After A Previous Intravenous Dose Optimization
NCT06224270	Phase 4	WITHDRAWN	Study of Response to Zoster Vaccine in Adults with Inflammatory Bowel Disease Treated with Medications
NCT06346288	Phase 4	COMPLETED	A Study to Assess the Concentrations of Risankizumab in the Breast Milk of Adult Lactating Women With Inflammatory Bowel Disease
NCT06584162	Phase 4	RECRUITING	Subcutaneous Interval Lengthening of Vedolizumab for Economic Research
NCT06788340	Phase 4	NOT_YET_RECRUITING	MOdel-Informed Precision Dosing of Ustekinumab and VEdolizumab in Inflammatory Bowel Disease
NCT06794944	Phase 4	NOT_YET_RECRUITING	Use of Fidaxomicin Compared to Vancomycin for Decolonization of C. Difficile in Patients With Inflammatory Bowel Disease
NCT07161297	Phase 4	NOT_YET_RECRUITING	Remimazolam for Colonoscopy in IBD Patients
NCT07612267	Phase 4	RECRUITING	A Study to Measure Mirikizumab Levels in Breast Milk of Lactating Participants Receiving Mirikizumab Therapeutically for an Approved Indication
NCT07673497	Phase 4	COMPLETED	Can Vitamin D Replacement Correct Chronic Disease Anemia?
NCT07737665	Phase 4	RECRUITING	Efficacy of Melatonin Treatment on Sleep Quality Improvement in Inflammatory Bowel Disease Patients With Clinical Remission
NCT02399566	Phase 4	UNKNOWN	Clinical Trial of Erlotinib and Pemetrexed for Maintenance Treatment in Lung Adenocarcinoma
NCT02804646	Phase 4	UNKNOWN	Endostar Durative Transfusion Combined With Chemotherapy in the Treatment of Advanced Lung Adenocarcinoma
NCT00868088	Phase 4	COMPLETED	Photodynamic Therapy to Treat Actinic Damage in Patients With Squamous Cell Carcinoma (SCC) of the Lip
NCT02088515	Phase 4	COMPLETED	Nedaplatin (Jiebaishu®) Combined With Docetaxel for Advanced Lung Squamous Cell Carcinoma
NCT02151149	Phase 4	COMPLETED	Safety and Efficacy Study of Abraxane in Combination With Carboplatin to Treat Advanced NSCL Cancer in the Elderly
NCT03388931	Phase 4	WITHDRAWN	Radiotherapy Dose Escalation in Locally Advanced Squamous Cell Carcinoma of the Larynx or Hypopharynx

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for TLR4 across ~30M SureChEMBL compounds — explore on Sugi Predict.