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
• Clinical variants (ClinVar): 123 total
• Phenotypes (HPO): 85
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_138554

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: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000355622, ENST00000394487, ENST00000472304, ENST00000490685

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
ENSE00003979004	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.

FANTOM5 promoters (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

273 total, 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

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

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)

95 targeting TLR4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

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

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)

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 (138 total): strand 36, repeat 18, helix 18, sequence variant 18, turn 12, 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.

PDB	Method	Resolution (Å)
2Z62	X-RAY DIFFRACTION	1.7
2Z66	X-RAY DIFFRACTION	1.9
2Z63	X-RAY DIFFRACTION	2
8WO1	ELECTRON MICROSCOPY	2.24
3UL7	X-RAY DIFFRACTION	2.37
4G8A	X-RAY DIFFRACTION	2.4
3UL9	X-RAY DIFFRACTION	2.45
3UL8	X-RAY DIFFRACTION	2.5
2Z65	X-RAY DIFFRACTION	2.7
9J03	ELECTRON MICROSCOPY	2.7
8WTA	ELECTRON MICROSCOPY	2.9
3FXI	X-RAY DIFFRACTION	3.1
3ULA	X-RAY DIFFRACTION	3.6
5NAM	SOLUTION NMR
5NAO	SOLUTION NMR

Predicted structure (AlphaFold)

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

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): 29–40, 281–306, 390–391, 583–609, 585–627

Glycosylation sites (10): 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+);
456	partially diminishes nf-kappa-b activation induced by ni(2+). strongly reduces nf-kappa-b activation induced by ni(2+);
458	partially diminishes nf-kappa-b activation induced by ni(2+). strongly reduces nf-kappa-b activation induced by ni(2+);
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 pathways

ID	Pathway
R-HSA-1236974	ER-Phagosome pathway
R-HSA-140534	Caspase activation via Death Receptors in the presence of ligand
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-2562578	TRIF-mediated programmed cell death
R-HSA-5602498	MyD88 deficiency (TLR2/4)
R-HSA-5603041	IRAK4 deficiency (TLR2/4)
R-HSA-5686938	Regulation of TLR by endogenous ligand
R-HSA-936964	Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)
R-HSA-937041	IKK complex recruitment mediated by RIP1
R-HSA-937072	TRAF6-mediated induction of TAK1 complex within TLR4 complex
R-HSA-9707616	Heme signaling
R-HSA-975163	IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation
R-HSA-9820960	Respiratory syncytial virus (RSV) attachment and entry
R-HSA-9824878	Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7
R-HSA-9833110	RSV-host interactions
R-HSA-9918481	Dengue Virus-Host Interactions

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 (102): toll-like receptor signaling pathway (GO:0002224), wound healing involved in inflammatory response (GO:0002246), B cell proliferation involved in immune response (GO:0002322), nitric oxide production involved in inflammatory response (GO:0002537), regulation of dendritic cell cytokine production (GO:0002730), MyD88-dependent toll-like receptor signaling pathway (GO:0002755), growth plate cartilage morphogenesis (GO:0003422), nitric oxide biosynthetic process (GO:0006809), phagocytosis (GO:0006909), inflammatory response (GO:0006954), immune response (GO:0006955), JNK cascade (GO:0007254), gene expression (GO:0010467), positive regulation of platelet activation (GO:0010572), positive regulation of gene expression (GO:0010628), astrocyte development (GO:0014002), microglia differentiation (GO:0014004), positive regulation of smooth muscle cell migration (GO:0014911), detection of fungus (GO:0016046), positive regulation of B cell proliferation (GO:0030890), 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), positive regulation of stress-activated MAPK cascade (GO:0032874)

GO Molecular Function (10): 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), NAD+ nucleosidase activity, cyclic ADP-ribose generating (GO:0061809)

GO Cellular Component (14): 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), endosome (GO:0005768), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-13 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
B cell proliferation	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
B cell activation involved in immune response	1
immune response	1
production of molecular mediator involved in inflammatory response	1
dendritic cell cytokine production	1
regulation of leukocyte mediated immunity	1
regulation of cytokine production involved in immune response	1
toll-like receptor signaling pathway	1
growth plate cartilage development	1
cartilage morphogenesis	1
biosynthetic process	1
nitric oxide metabolic process	1
endocytosis	1
defense response	1
immune system process	1
response to stimulus	1
MAPK cascade	1
macromolecule biosynthetic process	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
glial cell development	1
astrocyte differentiation	1
central nervous system development	1
glial cell differentiation	1
macrophage differentiation	1
smooth muscle cell migration	1
regulation of smooth muscle cell migration	1
positive regulation of cell migration	1

Protein interactions and networks

STRING

6826 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLR4	LY96	Q9Y6Y9	999
TLR4	HMGB1	P09429	999
TLR4	IFNB1	P01574	999
TLR4	TIRAP	P58753	999
TLR4	IRAK1	P51617	998
TLR4	SCARB1	Q8WTV0	997
TLR4	TRAF6	Q9Y4K3	997
TLR4	SCARB2	Q14108	996
TLR4	CD36	P16671	996
TLR4	HSPA4	P34932	995
TLR4	HSPD1	P10809	995
TLR4	FN1	P02751	995
TLR4	RETN	Q9HD89	993
TLR4	NOX4	Q9NPH5	993
TLR4	MYD88	P78397	993

IntAct

61 interactions, top by confidence:

A	B	Type	Score
TLR4	TIRAP	psi-mi:“MI:0915”(physical association)	0.810
TLR4	TIRAP	psi-mi:“MI:0914”(association)	0.810
TIRAP	TLR4	psi-mi:“MI:0914”(association)	0.810
MYD88	TLR4	psi-mi:“MI:0915”(physical association)	0.760
TLR4	MYD88	psi-mi:“MI:0915”(physical association)	0.760
LY96	TLR4	psi-mi:“MI:0915”(physical association)	0.740
TLR4	LY96	psi-mi:“MI:0915”(physical association)	0.740
TLR4	TLR4	psi-mi:“MI:0915”(physical association)	0.690
TLR4	NOX4	psi-mi:“MI:0915”(physical association)	0.680
TLR4	TICAM2	psi-mi:“MI:0915”(physical association)	0.680
TLR4	HMGB1	psi-mi:“MI:0915”(physical association)	0.600
HMGB1	TLR4	psi-mi:“MI:2364”(proximity)	0.600
TLR4	HMGB1	psi-mi:“MI:0914”(association)	0.600
TLR4	MBL2	psi-mi:“MI:0407”(direct interaction)	0.560
TNC	TLR4	psi-mi:“MI:0407”(direct interaction)	0.540
TNC	TLR4	psi-mi:“MI:0915”(physical association)	0.540

BioGRID (87): UBQLN1 (Two-hybrid), TICAM1 (Affinity Capture-Western), TICAM2 (Affinity Capture-Western), TLR4 (Affinity Capture-Western), CAV1 (Affinity Capture-Western), TLR4 (Two-hybrid), TLR4 (Affinity Capture-Western), SIGIRR (Affinity Capture-Western), TLR4 (Co-localization), TLR4 (Co-localization), TLR4 (Two-hybrid), MYD88 (Reconstituted Complex), TLR4 (Affinity Capture-Western), TRIM44 (Affinity Capture-Western), TLR4 (Co-localization)

ESM2 similar proteins: A2RT62, A4D1F6, A4IIK1, A6H6A4, A6NIV6, A6NM36, C0STK7, D3ZXS4, F1R6I3, O00206, O93233, P0C895, P58727, Q0PV50, Q32KX5, Q38SD2, Q3KQF4, Q3TX51, Q3UHC2, Q3UV48, Q3ZC49, Q4R6F0, Q58A48, Q5BKY1, Q5MJ12, Q5TJ59, Q65YW8, Q65Z91, Q66HD6, Q68Y56, Q6AXL3, Q6GLE8, Q6R5N8, Q6ZNQ3, Q86X40, Q8BGI7, Q8C0R9, Q8K3W2, Q8N456, Q8SPE8

Diamond homologs: A2ARI4, A3KNN3, A4IFA6, A6H789, A6H793, A6NJW4, A8WHP9, D4AC13, E5DHB5, E7FE13, F1MLX5, F1MT22, F7D3V9, G5EFX6, O00206, O02833, O14498, O35367, O35930, O46378, O46379, O46542, O62702, O75093, O75473, O88279, O88280, O94769, O94898, P07359, P07585, P0DKB5, P0DM44, P21793, P23515, P24014, P28675, P51885, P51886, P51890

SIGNOR signaling

25 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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 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	161.8×	1e-12
IRAK4 deficiency (TLR2/4)	7	153.7×	1e-12
Regulation of TLR by endogenous ligand	5	95.5×	6e-08
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	7	41.0×	2e-08
ER-Phagosome pathway	7	34.9×	4e-08
Adaptive Immune System	7	8.0×	3e-04
Innate Immune System	6	5.9×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of toll-like receptor 4 signaling pathway	5	170.9×	3e-08
toll-like receptor 4 signaling pathway	5	90.8×	4e-07
positive regulation of interleukin-1 beta production	6	53.6×	3e-07
positive regulation of interleukin-8 production	5	42.1×	9e-06
positive regulation of interleukin-6 production	6	34.5×	2e-06
positive regulation of tumor necrosis factor production	5	26.4×	4e-05
positive regulation of ERK1 and ERK2 cascade	7	20.5×	4e-06
cellular response to lipopolysaccharide	5	16.9×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	84
Likely benign	20
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

401 predictions. Top by Δscore:

Variant	Effect	Δscore
9:117704563:GAGGT:G	donor_loss	1.0000
9:117704564:AGGT:A	donor_loss	1.0000
9:117704566:G:C	donor_loss	1.0000
9:117704563:GAG:G	donor_gain	0.9900
9:117704566:G:GG	donor_gain	0.9900
9:117704562:GGAG:G	donor_gain	0.9800
9:117704563:GAGG:G	donor_gain	0.9800
9:117705401:A:AG	donor_gain	0.9700
9:117704537:G:GT	donor_gain	0.9400
9:117705398:G:GG	donor_gain	0.9400
9:117705397:A:G	donor_gain	0.9200
9:117710168:T:TA	donor_gain	0.8400
9:117710169:A:AA	donor_gain	0.8400
9:117708337:T:TA	donor_gain	0.8300
9:117708338:A:AA	donor_gain	0.8300
9:117705380:GATA:G	donor_gain	0.8200
9:117708336:GTA:G	donor_gain	0.8200
9:117712388:GGT:G	acceptor_gain	0.8200
9:117704561:TGGAG:T	donor_gain	0.8100
9:117704562:GGAGG:G	donor_gain	0.8100
9:117712383:CTGTA:C	acceptor_loss	0.8100
9:117712384:TGTA:T	acceptor_loss	0.8100
9:117712385:GTAG:G	acceptor_loss	0.8100
9:117712386:TAGGT:T	acceptor_loss	0.8100
9:117712387:A:T	acceptor_loss	0.8100
9:117704564:AG:A	donor_gain	0.8000
9:117704565:GG:G	donor_gain	0.8000
9:117712379:A:AG	acceptor_loss	0.8000
9:117705375:T:G	donor_gain	0.7300
9:117708590:AT:A	acceptor_gain	0.7300

AlphaMissense

5580 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:117714161:T:A	V678D	0.999
9:117714262:T:C	F712L	0.999
9:117714264:T:A	F712L	0.999
9:117714264:T:G	F712L	0.999
9:117714157:T:C	F677L	0.998
9:117714159:T:A	F677L	0.998
9:117714159:T:G	F677L	0.998
9:117714189:G:C	W687C	0.998
9:117714189:G:T	W687C	0.998
9:117714203:T:C	L692P	0.998
9:117714246:C:G	C706W	0.998
9:117714291:C:A	N721K	0.998
9:117714291:C:G	N721K	0.998
9:117714332:T:A	V735D	0.998
9:117714364:T:A	W746R	0.998
9:117714364:T:C	W746R	0.998
9:117714366:G:C	W746C	0.998
9:117714366:G:T	W746C	0.998
9:117714389:C:A	A754D	0.998
9:117714560:T:C	L811P	0.998
9:117714187:T:A	W687R	0.997
9:117714187:T:C	W687R	0.997
9:117714257:G:T	R710I	0.997
9:117714258:A:C	R710S	0.997
9:117714258:A:T	R710S	0.997
9:117714316:A:C	S730R	0.997
9:117714318:C:A	S730R	0.997
9:117714318:C:G	S730R	0.997
9:117714341:C:T	S738F	0.997
9:117714378:A:C	E750D	0.997

dbSNP variants (sampled 300 via entrez): RS1000071461 (9:117711708 T>A,C), RS1000456320 (9:117716773 A>G), RS1000460741 (9:117713194 C>T), RS1000596357 (9:117708521 C>A), RS1001216111 (9:117720431 C>G,T), RS1001309462 (9:117720178 A>G), RS1001462626 (9:117715258 C>A), RS1002011198 (9:117708466 C>A,G), RS1002034544 (9:117709174 A>G), RS1002123996 (9:117721131 A>C,G), RS1002149165 (9:117708906 C>T), RS1002641845 (9:117707180 G>C), RS1002716921 (9:117719901 C>G,T), RS1002868086 (9:117715537 C>G,T), RS1003199931 (9:117716770 T>C)

Disease associations

OMIM: gene MIM:603030 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
inflammatory bowel disease	Limited	Autosomal recessive

Mondo (5): lung adenocarcinoma (MONDO:0005061), squamous cell carcinoma (MONDO:0005096), COPD, severe early onset (MONDO:0011751), hereditary angioedema with normal C1Inh (MONDO:0100567), inflammatory bowel disease (MONDO:0005265)

Orphanet (2): Hereditary angioedema with normal C1Inh (Orphanet:528647), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

85 total (30 of 85 shown, 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

GWAS associations

48 associations (top):

Study	Trait	p-value
GCST001762_412	Obesity-related traits	3.000000e-06
GCST002444_4	Plasma omega-6 polyunsaturated fatty acid levels (dihomo-gamma-linolenic acid)	1.000000e-06
GCST002540_1	Osteoarthritis biomarkers	1.000000e-06
GCST002783_307	Body mass index	4.000000e-10
GCST002783_34	Body mass index	3.000000e-11
GCST002783_612	Body mass index	8.000000e-10
GCST003075_137	Cognitive decline rate in late mild cognitive impairment	8.000000e-07
GCST003075_138	Cognitive decline rate in late mild cognitive impairment	3.000000e-07
GCST003075_16	Cognitive decline rate in late mild cognitive impairment	1.000000e-06
GCST003075_35	Cognitive decline rate in late mild cognitive impairment	6.000000e-07
GCST004093_33	Prostate-specific antigen levels	2.000000e-08
GCST004495_112	BMI (adjusted for smoking behaviour)	1.000000e-08
GCST004495_76	BMI (adjusted for smoking behaviour)	7.000000e-07
GCST004497_53	Body mass index (joint analysis main effects and smoking interaction)	1.000000e-08
GCST004497_54	Body mass index (joint analysis main effects and smoking interaction)	2.000000e-06
GCST004499_72	BMI in non-smokers	7.000000e-09
GCST004499_73	BMI in non-smokers	2.000000e-06
GCST004557_14	Body mass index	1.000000e-08
GCST004557_199	Body mass index	2.000000e-06
GCST004557_228	Body mass index	1.000000e-08
GCST004557_98	Body mass index	9.000000e-07
GCST004558_11	Body mass index (joint analysis main effects and physical activity interaction)	2.000000e-08
GCST004558_148	Body mass index (joint analysis main effects and physical activity interaction)	2.000000e-08
GCST004558_170	Body mass index (joint analysis main effects and physical activity interaction)	3.000000e-06
GCST004558_96	Body mass index (joint analysis main effects and physical activity interaction)	3.000000e-06
GCST004559_129	Body mass index in physically active individuals	6.000000e-06
GCST004559_49	Body mass index in physically active individuals	9.000000e-06
GCST004559_9	Body mass index in physically active individuals	5.000000e-08
GCST004559_91	Body mass index in physically active individuals	1.000000e-07
GCST005232_151	Neuroticism	1.000000e-11

EFO canonical traits (22, from GWAS)

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 (2)

Descriptor	Name	Tree numbers
D002294	Carcinoma, Squamous Cell	C04.557.470.200.400; C04.557.470.700.400
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)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 429,451 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL34259	METHOTREXATE	4	398,396
CHEMBL5314354	POLYMYXIN B	4
CHEMBL723	CARVEDILOL	4	30,225
CHEMBL225157	RESATORVID	3	420
CHEMBL3301672	ERITORAN TETRASODIUM	3	51
CHEMBL501259	ERITORAN	3	359

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

6 annotations.

Variant	Type	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

8 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
rs4986791	TLR4		0.00	0
rs5030728	TLR4	3	3.25	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs1927911	TLR4		0.00	0
rs10759932	TLR4		0.00	0

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

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

218 with measured affinity, of 1171 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
[(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
(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
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
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
(11R,12R,13R,14S)-13-cyclopentyl-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
ethyl (6R)-6-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate	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	0.6800	uM
2-[11,17,23-tris(diaminomethylideneamino)-25,26,27-tripropoxy-5-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3(28),4,6,9(27),10,12,15,17,19(26),21,23-dodecaenyl]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	0.7000	uM
(7R)-7-(4-propylcyclohexyl)-6,7,8,8a-tetrahydro-5H-naphthalene-1,3-dione	1768717: Inhibition of TLR4 (unknown origin) by sandwich ELISA method	ic50	0.7300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	increases response to substance, decreases secretion, affects localization, increases phosphorylation, increases cleavage (+12 more)	48
Tobacco Smoke Pollution	decreases reaction, increases expression, decreases expression	12
lipopolysaccharide, Escherichia coli O111 B4	affects reaction, affects cotreatment, increases response to substance, decreases reaction, increases expression (+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, affects binding, increases expression, increases secretion, decreases expression (+3 more)	7
Resveratrol	decreases reaction, increases expression, increases reaction, decreases activity, affects response to substance (+6 more)	5
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases expression, decreases reaction	5
Quercetin	decreases expression, increases reaction, affects expression, affects cotreatment, decreases reaction (+1 more)	5
Particulate Matter	decreases expression, increases abundance, increases expression, decreases reaction	5
Cadmium	decreases expression, increases expression, decreases reaction	4
Paraquat	decreases reaction, increases expression, affects reaction	4
Progesterone	affects cotreatment, decreases reaction, increases expression	4
Valproic Acid	decreases methylation, increases expression, decreases expression	4
Cadmium Chloride	increases reaction, increases phosphorylation, increases expression	4
bisphenol A	increases reaction, affects binding, increases expression	3
nuciferine	decreases reaction, 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 localization, increases reaction, decreases expression, affects reaction, increases expression	3
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression, increases expression	3
Smoke	decreases expression, increases expression	3
Tetradecanoylphorbol Acetate	affects reaction, increases secretion, affects cotreatment, decreases reaction, increases expression	3
1-(3,4-dihydroxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one	affects binding, decreases reaction, increases reaction	2
sulforaphane	increases expression	2
sodium arsenite	decreases expression	2
cobaltous chloride	increases secretion, affects binding, increases activity, affects reaction	2
epigallocatechin gallate	affects cotreatment, decreases reaction, increases expression	2
(+)-JQ1 compound	decreases expression, affects cotreatment	2
Atorvastatin	affects cotreatment, decreases expression, increases expression	2
Acetaminophen	affects cotreatment, increases expression, decreases expression	2
Acetylcysteine	decreases reaction, increases expression, increases reaction, decreases expression	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)

598 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00167882	PHASE4	COMPLETED	The Influence of 5-Aminosalicylates on Thiopurine Metabolite Levels
NCT00205062	PHASE4	TERMINATED	Positron Emission Tomography (PET)-Computed Tomography (CT) in Inflammatory Bowel Disease (IBD)
NCT00567593	PHASE4	COMPLETED	Gene Regulation by Thiazolidinediones
NCT00746395	PHASE4	COMPLETED	Randomized, Placebo-controlled Trial of Lubiprostone as a Preparation for Capsule Endoscopy
NCT01034358	PHASE4	COMPLETED	Immune Response to the Human Papillomavirus Vaccine in Young Women With Inflammatory Bowel Disease
NCT01056913	PHASE4	COMPLETED	NITI CAR27 (ColonRing) Compression Anastomosis in Colorectal Surgery
NCT01067547	PHASE4	COMPLETED	A Trial of Iron Replacement in Patients With Iron Deficiency.
NCT01341808	PHASE4	COMPLETED	Immunogenicity of Hepatitis A Vaccine in Inflammatory Bowel Disease (IBD) Patients
NCT01908283	PHASE4	COMPLETED	Induction of Immunity Against Streptococcus Pneumoniae in Adults With Inflammatory Bowel Disease
NCT01934088	PHASE4	COMPLETED	Satisfaction With Nurse Administered Propofol Sedation vs. Midazolam With Fentanyl Sedation for Endoscopy
NCT02162862	PHASE4	COMPLETED	Treating Disrupted Sleep in Individuals With Inflammatory Bowel Disease
NCT02248337	PHASE4	COMPLETED	Low Volume Colon Preparation for IBD
NCT02281799	PHASE4	WITHDRAWN	Thiopurine Induced Pancreatitis in IBD Patients
NCT02392286	PHASE4	TERMINATED	Corticosteroid Dosage for Crohn’s Disease Flare
NCT02437591	PHASE4	COMPLETED	Study to Evaluate the Pharmacokinetics of Fidaxomicin in Inflammatory Bowel Disease (IBD) Subjects With Clostridium Difficile Infection (CDI)
NCT02453776	PHASE4	COMPLETED	Precision Dosing of Infliximab Versus Conventional Dosing of Infliximab
NCT02461758	PHASE4	COMPLETED	Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory Bowel Disease Patients
NCT02566889	PHASE4	TERMINATED	An Efficacy and Safety Study of Infliximab Dose Escalation in Pediatric Participants With Inflammatory Bowel Disease
NCT02774057	PHASE4	UNKNOWN	Trial of Captafer® vs. Oral Iron Sulfate in the Treatment of Iron Deficiency Anemia in Patients With IBD
NCT02806206	PHASE4	UNKNOWN	Prucalopride Prior to Small Bowel Capsule Endoscopy
NCT02946203	PHASE4	COMPLETED	Comparison of VoLumen and Breeza Oral Contrast Agents in Pediatric Patients
NCT02994836	PHASE4	COMPLETED	GIS-SUSANTI-TNF-2015 (Anti-TNF Discontinuation )
NCT03220841	PHASE4	UNKNOWN	Stricture Definition and Treatment (STRIDENT) Drug Therapy Study
NCT03351972	PHASE4	COMPLETED	Differences in Preparation for Small Bowel Capsule Endoscopy
NCT03466983	PHASE4	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	PHASE4	TERMINATED	Shingrix Vaccine in Patients With Moderate to Severe Ulcerative Colitis on Tofacitinib
NCT03629379	PHASE4	COMPLETED	Response to Ustekinumab for Anti-tnf Induced Psoriasiform Skin Lesions
NCT03723447	PHASE4	COMPLETED	Intraoperative TAP Block With Bupivacaine/Dexamethasone Against Liposomal Bupivacaine (Exparel®)
NCT03798691	PHASE4	COMPLETED	Immunogenicity of Herpes Zoster Subunit Vaccine in Inflammatory Bowel Disease Patients Treated With Vedolizumab
NCT03860012	PHASE4	UNKNOWN	Folic Acid in Pediatric Inflammatory Bowel Disease
NCT03885713	PHASE4	COMPLETED	Identification of Predictive Biomarkers for Response to Biologic Therapies and Tofacitinib in Inflammatory Bowel Disease
NCT03917303	PHASE4	RECRUITING	Control Crohn Safe Trial
NCT04045782	PHASE4	COMPLETED	Evaluation of the Safety and Effectiveness of Switching From Humira® to Imraldi® in Flanders
NCT04304950	PHASE4	COMPLETED	Chronotherapy in Inflammatory Bowel Disease
NCT04626947	PHASE4	TERMINATED	Prevention of Recurrent Clostridium Difficile Infection (CDI) in Patients With Inflammatory Bowel Disease (IBD).
NCT04646187	PHASE4	ENROLLING_BY_INVITATION	De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
NCT04835506	PHASE4	ACTIVE_NOT_RECRUITING	Proactive Infliximab Optimization Using a Pharmacokinetic Dashboard Versus Standard of Care in Patients With Inflammatory Bowel Disease: The OPTIMIZE Trial
NCT04982172	PHASE4	COMPLETED	Model-informed Dose De-escalation of Infliximab in Patients With Inflammatory Bowel Diseases
NCT05180175	PHASE4	COMPLETED	The Nordic IBD Treatment Strategy Trial
NCT05280405	PHASE4	UNKNOWN	Early Proactive Therapeutic Drug Monitoring of Infliximab in Children: EPIC Study