THRB

Summary

THRB (thyroid hormone receptor beta, HGNC:11799) is a protein-coding gene on chromosome 3p24.2, encoding Thyroid hormone receptor beta (P10828). Nuclear hormone receptor that can act as a repressor or activator of transcription.

The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Mutations in this gene are known to be a cause of generalized thyroid hormone resistance (GTHR), a syndrome characterized by goiter and high levels of circulating thyroid hormone (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). Several alternatively spliced transcript variants encoding the same protein have been observed for this gene.

Source: NCBI Gene 7068 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thyroid hormone resistance, generalized, autosomal dominant (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 80 (top 1% of genes corpus-wide)
• Clinical variants (ClinVar): 756 total — 47 pathogenic, 34 likely-pathogenic (top 4% of genes corpus-wide)
• Regional missense constraint (gnomAD): 2 of 5 regions constrained (≈34% of expected missense variation)
• GTEx eGene: eQTL in 19 tissues, sQTL in 4 (q < 0.05)
• Phenotypes (HPO): 39
• Drug target: yes — 3 curated mechanism-of-action drugs, 4 via a complex or family; 117 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 1 — Resmetirom
• Approved drugs acting on a complex or family including it: 3 — Dextrothyroxine, Levothyroxine Sodium, Liothyronine (Thyroid hormone receptor)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.43 (moderately constrained)
• Transcription factor: yes — 66 downstream targets (CollecTRI)
• MANE Select transcript: NM_001354712

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11799
Approved symbol	THRB
Name	thyroid hormone receptor beta
Location	3p24.2
Locus type	gene with protein product
Status	Approved
Aliases	THRB1, THRB2, NR1A2, THR1, ERBA-BETA, GRTH, TRbeta, TRb, c-erbA-beta, c-erbA-2, THRbeta, TRbeta1, THRbeta1, Thrbeta2
Ensembl gene	ENSG00000151090
Ensembl biotype	protein_coding
OMIM	190160
Entrez	7068

Gene structure

Transcript identifiers

Ensembl transcripts: 57 — 54 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000646209

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 2, TSL 3: 1, TSL 4: 2, TSL 5: 2

ENST00000646209, ENST00000280696, ENST00000356447, ENST00000396671, ENST00000413780, ENST00000416420, ENST00000418247, ENST00000428492, ENST00000431815, ENST00000447414, ENST00000447875, ENST00000453729, ENST00000642307, ENST00000643772, ENST00000644321, ENST00000645139, ENST00000646300, ENST00000646432, ENST00000646966, ENST00000851503, ENST00000851504, ENST00000851505, ENST00000851506, ENST00000851507, ENST00000851508, ENST00000851509, ENST00000851510, ENST00000851511, ENST00000851512, ENST00000851513, ENST00000851514, ENST00000851515, ENST00000851516, ENST00000851517, ENST00000851518, ENST00000851519, ENST00000851520, ENST00000851521, ENST00000851522, ENST00000851523, ENST00000851524, ENST00000965290, ENST00000965291, ENST00000965292, ENST00000965293, ENST00000965294, ENST00000965295, ENST00000965296, ENST00000965297, ENST00000965298, ENST00000965299, ENST00000965300, ENST00000965301, ENST00000965302, ENST00000987153, ENST00001106377, ENST00001117907

RefSeq mRNA: 18 — MANE Select: NM_001354712 NM_000461, NM_001128176, NM_001128177, NM_001252634, NM_001354708, NM_001354709, NM_001354710, NM_001354711, NM_001354712, NM_001354713, NM_001354714, NM_001354715, NM_001374822, NM_001374823, NM_001374824, NM_001374825, NM_001374826, NM_001374827

CCDS: CCDS2641

Canonical transcript exons

ENST00000646209 — 11 exons

Exon	Start	End
ENSE00001073517	24133316	24133462
ENSE00001073518	24146675	24146822
ENSE00001073519	24143501	24143706
ENSE00001395906	24337300	24337371
ENSE00001397913	24228938	24229001
ENSE00001612462	24297226	24297371
ENSE00001642867	24152390	24152490
ENSE00001718132	24127499	24127757
ENSE00003540357	24190074	24190334
ENSE00003901767	24117153	24123125
ENSE00004801686	24494652	24494850

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 98.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.6473 / max 244.0114, expressed in 979 samples.

Highest expression (Bgee): Brodmann (1909) area 23, middle temporal gyrus, tibia, postcentral gyrus, parietal lobe.

Genetic regulation across tissues (GTEx eQTL / sQTL)

THRB is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 4 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 23 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Mucosa	eqtl	2.0e-34	-0.57	3:24447374:C:A
Heart Atrial Appendage	eqtl	3.9e-11	+0.38	3:24423464:G:A
Heart Left Ventricle	eqtl	8.1e-07	+0.16	3:24422421:A:G
Skin Sun Exposed Lower leg	eqtl	1.4e-06	+0.15	3:24377444:A:AG
Esophagus Muscularis	eqtl	8.8e-06	+0.13	3:24363559:C:T
Artery Aorta	eqtl	1.8e-05	-0.11	3:24213259:T:A
Skin Sun Exposed Lower leg	sqtl	1.8e-05	-0.37	3:24393033:A:G
Nerve Tibial	eqtl	8.0e-05	-0.16	3:24427979:C:A
Esophagus Gastroesophageal Junction	eqtl	6.7e-04	+0.12	3:24358637:C:T
Spleen	eqtl	1.3e-03	+0.29	3:24190544:C:T
Cells Cultured fibroblasts	eqtl	1.8e-03	-0.11	3:24683153:T:TGTAA
Muscle Skeletal	eqtl	2.0e-03	-0.32	3:24482418:A:C
Thyroid	eqtl	3.6e-03	-0.19	3:24489809:T:C
Skin Not Sun Exposed Suprapubic	sqtl	1.2e-02	-0.33	3:24380522:T:C
Brain Cerebellum	eqtl	1.2e-02	-0.13	3:24288792:G:A
Brain Caudate basal ganglia	sqtl	1.3e-02	-1.94	3:24477601:T:C
Skin Not Sun Exposed Suprapubic	eqtl	1.5e-02	+0.14	3:24380522:T:C
Small Intestine Terminal Ileum	eqtl	1.7e-02	-0.60	3:25461005:C:T
Adipose Subcutaneous	eqtl	2.1e-02	+0.14	3:24428302:C:T
Stomach	eqtl	2.3e-02	+0.40	3:24270252:C:T

FANTOM5 promoters

showing 10 of 20 alternative TSS:

Promoter ID	TPM avg	Samples expressed
41482	2.9023	803
41483	0.7282	358
41487	0.5479	97
41481	0.3878	211
41485	0.3807	191
41486	0.1694	75
41488	0.1522	85
41484	0.1136	51
41465	0.0534	11
41472	0.0507	7

Top tissues by expression

showing 100 of 296 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	98.54	gold quality
middle temporal gyrus	UBERON:0002771	97.50	gold quality
tibia	UBERON:0000979	96.43	gold quality
postcentral gyrus	UBERON:0002581	95.94	gold quality
parietal lobe	UBERON:0001872	95.65	gold quality
endothelial cell	CL:0000115	95.60	gold quality
superior frontal gyrus	UBERON:0002661	95.46	gold quality
entorhinal cortex	UBERON:0002728	94.14	gold quality
calcaneal tendon	UBERON:0003701	93.58	gold quality
mammary duct	UBERON:0001765	92.09	gold quality
tendon	UBERON:0000043	91.19	gold quality
parotid gland	UBERON:0001831	90.59	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.24	gold quality
primary visual cortex	UBERON:0002436	90.22	gold quality
descending thoracic aorta	UBERON:0002345	90.02	gold quality
renal medulla	UBERON:0000362	89.41	gold quality
thoracic aorta	UBERON:0001515	89.33	gold quality
occipital lobe	UBERON:0002021	89.32	gold quality
ascending aorta	UBERON:0001496	89.26	gold quality
seminal vesicle	UBERON:0000998	89.09	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.69	gold quality
synovial joint	UBERON:0002217	88.42	gold quality
epithelium of mammary gland	UBERON:0003244	88.13	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.89	gold quality
prefrontal cortex	UBERON:0000451	87.72	gold quality
aorta	UBERON:0000947	87.72	gold quality
frontal cortex	UBERON:0001870	87.47	gold quality
muscle of leg	UBERON:0001383	86.86	gold quality
mammary gland	UBERON:0001911	86.77	gold quality
thoracic mammary gland	UBERON:0005200	86.75	gold quality
adult organism	UBERON:0007023	86.61	gold quality
gastrocnemius	UBERON:0001388	86.57	gold quality
popliteal artery	UBERON:0002250	86.44	gold quality
tendon of biceps brachii	UBERON:0008188	86.41	gold quality
tibial artery	UBERON:0007610	86.40	gold quality
neocortex	UBERON:0001950	86.31	gold quality
lateral nuclear group of thalamus	UBERON:0002736	86.27	gold quality
artery	UBERON:0001637	86.03	gold quality
mucosa of sigmoid colon	UBERON:0004993	86.03	gold quality
temporal lobe	UBERON:0001871	85.78	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.69	gold quality
cerebral cortex	UBERON:0000956	85.54	gold quality
parietal pleura	UBERON:0002400	85.37	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	85.37	gold quality
right frontal lobe	UBERON:0002810	85.17	gold quality
skeletal muscle organ	UBERON:0014892	85.15	gold quality
pituitary gland	UBERON:0000007	85.13	gold quality
muscle organ	UBERON:0001630	85.13	gold quality
colonic mucosa	UBERON:0000317	85.06	gold quality
superficial temporal artery	UBERON:0001614	84.88	gold quality
jejunum	UBERON:0002115	84.59	gold quality
penis	UBERON:0000989	84.48	gold quality
buccal mucosa cell	CL:0002336	84.40	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.07	gold quality
right coronary artery	UBERON:0001625	83.92	gold quality
cingulate cortex	UBERON:0003027	83.88	gold quality
anterior cingulate cortex	UBERON:0009835	83.64	gold quality
telencephalon	UBERON:0001893	83.60	gold quality
saphenous vein	UBERON:0007318	83.40	gold quality
liver	UBERON:0002107	83.31	gold quality
coronary artery	UBERON:0001621	83.21	gold quality
mucosa of stomach	UBERON:0001199	83.18	gold quality
left coronary artery	UBERON:0001626	83.18	gold quality
vastus lateralis	UBERON:0001379	83.07	gold quality
biceps brachii	UBERON:0001507	83.00	gold quality
forebrain	UBERON:0001890	82.91	gold quality
sigmoid colon	UBERON:0001159	82.75	gold quality
jejunal mucosa	UBERON:0000399	82.71	gold quality
adenohypophysis	UBERON:0002196	82.51	gold quality
adipose tissue	UBERON:0001013	82.33	gold quality
pleura	UBERON:0000977	82.28	gold quality
connective tissue	UBERON:0002384	82.22	gold quality
lower esophagus	UBERON:0013473	82.21	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.21	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.19	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	82.03	gold quality
colonic epithelium	UBERON:0000397	81.89	gold quality
skeletal muscle tissue	UBERON:0001134	81.72	gold quality
urethra	UBERON:0000057	81.65	gold quality
Ammon’s horn	UBERON:0001954	81.23	gold quality
quadriceps femoris	UBERON:0001377	81.12	silver quality
cartilage tissue	UBERON:0002418	81.10	gold quality
right lobe of liver	UBERON:0001114	81.00	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.83	gold quality
cardia of stomach	UBERON:0001162	80.62	gold quality
corpus callosum	UBERON:0002336	80.53	gold quality
amygdala	UBERON:0001876	80.51	gold quality
lower lobe of lung	UBERON:0008949	80.26	gold quality
epithelium of nasopharynx	UBERON:0001951	80.10	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.01	gold quality
rectum	UBERON:0001052	79.75	gold quality
deltoid	UBERON:0001476	79.67	silver quality
brain	UBERON:0000955	79.50	gold quality
nucleus accumbens	UBERON:0001882	79.32	gold quality
colon	UBERON:0001155	79.21	gold quality
central nervous system	UBERON:0001017	79.12	gold quality
muscle tissue	UBERON:0002385	79.10	gold quality
large intestine	UBERON:0000059	78.92	gold quality
fundus of stomach	UBERON:0001160	78.89	gold quality
urinary bladder	UBERON:0001255	78.74	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	796.36
E-HCAD-25	yes	75.44
E-HCAD-35	yes	66.24
E-MTAB-7316	yes	24.02
E-CURD-119	yes	17.12
E-ANND-3	yes	12.30
E-GEOD-137537	no	3.19
E-GEOD-83139	no	3.05

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Postcentral gyrus	tissue	74.7
Prefrontal cortex	tissue	72.1
Cerebral cortex	tissue	72.1	low
Motor cortex	tissue	68.6
Retrosplenial and cingulate cortex	tissue	59.3
Hippocampal formation	tissue	57.0
Entorhinal cortex	tissue	57.0
Retrosplenial cortex	tissue	56.3
Insular cortex	tissue	55.5
Somatosensory cortex	tissue	53.4
Occipital cortex	tissue	48.9
Temporal cortex	tissue	45.9
Amygdala	tissue	33.0
Nucleus accumbens	tissue	30.9
Choroid plexus	tissue	30.1
Hippocampus	tissue	28.1	low
Tongue	tissue	25.3
Frontal cortex	tissue	22.5
Skeletal muscle	tissue	22.1	not detected
Basal ganglia	tissue	19.8	low
Caudate putamen	tissue	19.8
Ventral forebrain	tissue	19.6
Thalamus	tissue	19.0
Septum	tissue	18.9
Liver	tissue	18.8	not detected
Retina	tissue	18.6
Midbrain	tissue	17.3
Spinal cord	tissue	17.2
Superior colliculi	tissue	16.8
Pons	tissue	15.6
Hypothalamus	tissue	15.4
Locus coeruleus	tissue	15.3
Periaqueductal gray	tissue	15.2
Putamen	tissue	14.9
Medulla oblongata	tissue	14.4
Substantia nigra	tissue	13.9
Corpus callosum	tissue	13.9
Pituitary gland	tissue	13.5
Kidney	tissue	11.3	not detected
Adipose tissue	tissue	10.4	low
Olfactory bulb	tissue	9.7
Breast	tissue	9.3	low
Pancreas	tissue	8.5	not detected
Urinary bladder	tissue	8.3	not detected
Rectum	tissue	7.9	low
Stomach 1	tissue	7.8	low
Seminal vesicle	tissue	7.3	not detected
Heart muscle	tissue	7.2	not detected
Prostate	tissue	7.0	not detected
Parathyroid gland	tissue	6.8	not detected
Cerebellum	tissue	6.7	not detected
Smooth muscle	tissue	6.6	not detected
Endometrium 1	tissue	6.5	not detected
Skin 1	tissue	6.4	not detected
Colon	tissue	6.4	low
Esophagus	tissue	6.0	not detected
Salivary gland	tissue	5.8	not detected
Spleen	tissue	5.4	not detected
Lung	tissue	4.7	low
Adrenal gland	tissue	4.6	low

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Perirhinal gyrus (77.3), Superior temporal gyrus (74.9), Inferior temporal gyrus (73.0), Lingual gyrus (71.7), Fusiform gyrus (70.3).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 66 targets:

Target	Regulation
ACACA
ADAM2
ANGPTL3
APOA2	Repression
APOC2	Activation
APOC3
CAT
CCND1	Repression
CGA	Repression
CREB1	Repression
CTNNB1	Unknown
CYP27B1
DHCR24
E2F1	Activation
FGF21
FN1	Activation
GH1
GHRHR
GNAS
GPHA2
GTF2B
HCN4	Repression
HIF1A	Activation
ITGB3
KCND3
KCNMA1
LDLR	Unknown
MLXIPL	Activation
MMP12
MYH6

JASPAR motifs

Motif	Name	Family
MA1574.1	THRB	Thyroid hormone receptor-related factors (NR1)
MA1574.2	THRB	Thyroid hormone receptor-related factors (NR1)
MA1575.1	THRB	Thyroid hormone receptor-related factors (NR1)
MA1575.2	THRB	Thyroid hormone receptor-related factors (NR1)
MA1576.1	THRB	Thyroid hormone receptor-related factors (NR1)
MA1576.2	THRB	Thyroid hormone receptor-related factors (NR1)

JASPAR matrix evidence (PMIDs): PMID:19741045

Upstream regulators (CollecTRI, top): NEUROD1, PAX1, POU1F1, POU2F1, THRA, THRB

miRNA regulators (miRDB)

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

showing 30 of 391 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955

Functional genomics

gnomAD constraint: pLI 0.999, LOEUF 0.43, missense Z 3.72 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000646209 splits into 5 regions with different missense tolerance; 2 are missense-constrained (≈34% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
3:24,122,887–24,122,990	7 / 46.8	0.15	yes (p 5.9e-09)
3:24,122,991–24,123,119	36 / 51.7	0.70	no
3:24,123,120–24,133,417	45 / 156.2	0.29	yes (p 5.8e-19)
3:24,133,418–24,152,483	112 / 212.3	0.53	no
3:24,152,484–24,228,959	148 / 122.3	1.21	no

Literature-anchored findings (GeneRIF, showing 40)

• TR surfaces and conformations required to bind nuclear receptor corepressor (PMID:11818500)
• neurodevelopmental functions of thyroid hormone signaling (PMID:11861164)
• affected receptor amino acid sequences.lost their trans-activation function and exhibited dominant negative activity. (PMID:11889175)
• genetic analysis revealed a novel heterozygous missense mutation at codon 334 of thyroid hormone receptor beta1 in a family with resistance to thyroid hormone (PMID:11929097)
• a point mutation, not anticipated to occur in resistance to thyroid hormone, causes variable phenotypes. (PMID:12006711)
• Thrb(PV)/Thrb(PV) mice have severe hearing impairment that is already present at 3 weeks of age. This hearing loss is associated with disruption of postnatal morphogenesis of the tectorial membrane and organ of Corti. (PMID:12382103)
• x-ray crystal structures of two hTRbeta ligand-binding domains, Ala 317 Thr and Arg 316 His (PMID:12554782)
• expression of functionally impaired mutants of THRB1 in papillary carcinomas is rare (PMID:12843201)
• The crystal structure of human thyroid hormone receptor beta at 2.8-A resolution with GC-24 bound explains its agonist activity and unique isoform specificity. (PMID:14673100)
• Except for cardiac hypertrophy, the presence of a germline TR-beta mutation had surprisingly little effect on cardiac function. (PMID:14684607)
• thyroid hormone receptor-beta cell cycle-dependent expression regulates variable hormone sensitivity (PMID:14767065)
• partial dissociation of TR/retinoid X receptor heterodimer complex from the TRE is involved in the suppression of transcription induced by polychlorinated biphenyls (PMID:14985366)
• novel point mutation, a heterozygous transition c.1031G>C in exon 9 theoretically substituting Gly344Ala results in bone development retardation (PMID:15080770)
• developmental and tissue-specific expression of human thyroid hormone receptor beta1 5’-UTR mRNAs may regulate T3-responsiveness in target tissues by modulating TRbeta protein translation (PMID:15105435)
• Most patients with resistance to thyroid hormone carry a mutation in this gene. (PMID:15186611)
• unliganded TRbeta1 suppresses promoter activity driven by LXRalpha and its ligand, whereas transactivation by T3-bound TRbeta1 is not affected by LXRalpha in the presence or absence of oxysterols (PMID:15319359)
• two novel TRbeta mutations occurring in the same nucleotide (PMID:15598685)
• results suggested that T3 upregulates cellular proliferation on LNCaP cells but not other prostatic carcinoma cells and PZ-HPV-7 and CA-HPV-10 cells express the novel TRbeta1, which locates at cell nuclear membrane (PMID:15867011)
• a small subset of TRbeta mutations that arise in resistance to thyroid hormone syndrome inhibit both T3 binding and formation of TRbeta homodimers on thyroid hormone response elements (PMID:15886199)
• Modulation of hepatic TRbeta1, a key regulator of gene expression involved in lipid metabolism by soy proteins may be a novel mechanism by which soy components lower blood lipid level and exert their hypocholesterolemic actions. (PMID:15987841)
• Pituitary and peripheral tissue responses to graded doses of liothyronine in 5 affected members of a family with thyroid hormone resistance due to the common TRbeta mutation P453T are reported. (PMID:16099238)
• Association of TRbeta1 expression with growth pattern and the presence of K-ras mutations suggest that abnormalities in thyroid hormone signalling involving TRbeta1 play a role in the development of some types of colorectal adenocarcinomas (PMID:16231318)
• Thyroid hormone receptor (TR) D-domain has the potential to form functionally important extensions of the DNA-binding domain (DBD) and ligand-binding domain (LBD) or unfold to permit TRs to adapt to different DNA response elements. (PMID:16781732)
• The E333D TRbeta mutation is responsible for the resistance to thyroid hormone syndrome in a case report. (PMID:17177139)
• apo THRBs form tetramers in solution which dissociate into dimers upon thyroid hormone T3 binding (PMID:17260956)
• Mediates Akt activation by T3 in pancreatic beta cells. (PMID:17293442)
• These findings provide a molecular rationale for the role of hS14 in TR-dependent transcriptional activation of the expression of specific genes. (PMID:17418816)
• the two systems, TRs and IGF1/IGF1R could also be functionally associated. (PMID:17560756)
• an insertion mutation in thyroid hormone receptor-beta may have a role in thyroid hormone resistance (PMID:17596672)
• Generalized resistance to thyroid hormone with chronic thyroiditis with a novel mutation, G347A, of the TR beta gene. (PMID:17827792)
• hypermethylation of the TRbeta gene as an alternative gene silencing mechanism is highly prevalent in thyroid cancer (PMID:17911173)
• Activation of the thyroid hormone receptor beta/retinoid X receptor alpha heterodimer by T(3) stimulated expression of the hepatic leukemia factor, which increases HIF-1alpha gene expression. (PMID:18239067)
• We report the first case of a woman with resistance to thyroid hormone, which was found to be caused by a missense mutation (V349M) in the TR beta gene. (PMID:18363280)
• Furin overexpression in some types of hepatocellular carcinomas is TR dependent. (PMID:18467449)
• Mutational analysis of the TRRB gene allows definitive diagnosis of thyroid hormone resistance syndrome, potentially avoiding the need for protracted and expensive pituitary function testing. (PMID:18561095)
• As TRbeta(H435Y) has been found in both resistance to thyroid hormone and pituitary carcinoma, these results serve perhaps as the first example of chemical rescue that targets a mutant protein involved in multiple disease states. (PMID:18683837)
• In this work, a single surface mutation, D355R, was shown to be crucial for converting the modestly stable monomeric ligand binding domain of the human thyroid hormone receptor (TR LBD) into a stable dimer. (PMID:18798561)
• Analysis of the T3 receptor genes revealed 15 SNPs, including 7 novel. Only THRB-in9-G/A was associated with higher serum TSH in a large population of Danish twins. (PMID:18844476)
• Our findings suggest that flexibility plays an important role in interaction between the receptor & its coregulators, & point out important aspects of experimental design that should be addressed when using TRbeta ligand binding domain & its agonists. (PMID:19000767)
• the Thyroid hormone beta1 receptor mediates the T3 upregulation of protein synthesis and cell size, together with the cell proliferation and survival, playing a crucial role in the T3 regulation of the PI3K/Akt pathway. (PMID:19160403)

Cross-species orthologs

184 orthologs

Organism	Symbol	Gene ID
danio_rerio	thrb	ENSDARG00000021163
mus_musculus	Thrb	ENSMUSG00000021779
rattus_norvegicus	Thrb	ENSRNOG00000006649
drosophila_melanogaster	Hr96	FBGN0015240
caenorhabditis_elegans		WBGENE00001062
caenorhabditis_elegans		WBGENE00003608
caenorhabditis_elegans		WBGENE00003611
caenorhabditis_elegans		WBGENE00003614
caenorhabditis_elegans		WBGENE00003615
caenorhabditis_elegans		WBGENE00003617
caenorhabditis_elegans		WBGENE00003618
caenorhabditis_elegans		WBGENE00003620
caenorhabditis_elegans		WBGENE00003624
caenorhabditis_elegans		WBGENE00003632
caenorhabditis_elegans		WBGENE00003634
caenorhabditis_elegans		WBGENE00003638
caenorhabditis_elegans		WBGENE00003640
caenorhabditis_elegans		WBGENE00003641
caenorhabditis_elegans		WBGENE00003642
caenorhabditis_elegans		WBGENE00003643
caenorhabditis_elegans		WBGENE00003644
caenorhabditis_elegans		WBGENE00003645
caenorhabditis_elegans		WBGENE00003646
caenorhabditis_elegans		WBGENE00003648
caenorhabditis_elegans		WBGENE00003649
caenorhabditis_elegans		WBGENE00003651
caenorhabditis_elegans		WBGENE00003653
caenorhabditis_elegans		WBGENE00003655
caenorhabditis_elegans		WBGENE00003658
caenorhabditis_elegans		WBGENE00003660
caenorhabditis_elegans		WBGENE00003662
caenorhabditis_elegans	nhr-73	WBGENE00003663
caenorhabditis_elegans	nhr-77	WBGENE00003667
caenorhabditis_elegans		WBGENE00003669
caenorhabditis_elegans	nhr-81	WBGENE00003671
caenorhabditis_elegans	nhr-82	WBGENE00003672
caenorhabditis_elegans		WBGENE00003676
caenorhabditis_elegans		WBGENE00003677
caenorhabditis_elegans		WBGENE00003680
caenorhabditis_elegans		WBGENE00003682
caenorhabditis_elegans		WBGENE00003684
caenorhabditis_elegans		WBGENE00003685
caenorhabditis_elegans		WBGENE00003686
caenorhabditis_elegans		WBGENE00003688
caenorhabditis_elegans		WBGENE00003689
caenorhabditis_elegans		WBGENE00003692
caenorhabditis_elegans		WBGENE00003693
caenorhabditis_elegans		WBGENE00003694
caenorhabditis_elegans		WBGENE00003696
caenorhabditis_elegans		WBGENE00003698
caenorhabditis_elegans		WBGENE00003699
caenorhabditis_elegans		WBGENE00003700
caenorhabditis_elegans		WBGENE00003702
caenorhabditis_elegans		WBGENE00003704
caenorhabditis_elegans		WBGENE00003705
caenorhabditis_elegans		WBGENE00003707
caenorhabditis_elegans		WBGENE00003708
caenorhabditis_elegans		WBGENE00003712
caenorhabditis_elegans		WBGENE00003713
caenorhabditis_elegans		WBGENE00003714
caenorhabditis_elegans		WBGENE00003715
caenorhabditis_elegans		WBGENE00003716
caenorhabditis_elegans		WBGENE00003717
caenorhabditis_elegans		WBGENE00003718
caenorhabditis_elegans		WBGENE00003720
caenorhabditis_elegans		WBGENE00003721
caenorhabditis_elegans		WBGENE00003722
caenorhabditis_elegans		WBGENE00003723
caenorhabditis_elegans		WBGENE00003724
caenorhabditis_elegans		WBGENE00003725
caenorhabditis_elegans		WBGENE00003728
caenorhabditis_elegans		WBGENE00006471
caenorhabditis_elegans	unc-55	WBGENE00006790
caenorhabditis_elegans		WBGENE00007367
caenorhabditis_elegans		WBGENE00008056
caenorhabditis_elegans	nhr-165	WBGENE00008158
caenorhabditis_elegans		WBGENE00008208
caenorhabditis_elegans	nhr-169	WBGENE00008289
caenorhabditis_elegans		WBGENE00008309
caenorhabditis_elegans	nhr-174	WBGENE00008474
caenorhabditis_elegans		WBGENE00008619
caenorhabditis_elegans		WBGENE00008630
caenorhabditis_elegans		WBGENE00008778
caenorhabditis_elegans		WBGENE00008830
caenorhabditis_elegans		WBGENE00008884
caenorhabditis_elegans		WBGENE00008901
caenorhabditis_elegans	nhr-265	WBGENE00009608
caenorhabditis_elegans		WBGENE00010017
caenorhabditis_elegans		WBGENE00010180
caenorhabditis_elegans		WBGENE00010186
caenorhabditis_elegans		WBGENE00010215
caenorhabditis_elegans		WBGENE00010410
caenorhabditis_elegans		WBGENE00010600
caenorhabditis_elegans		WBGENE00010601
caenorhabditis_elegans		WBGENE00010602
caenorhabditis_elegans		WBGENE00010603
caenorhabditis_elegans		WBGENE00010604
caenorhabditis_elegans		WBGENE00011002
caenorhabditis_elegans		WBGENE00011150
caenorhabditis_elegans		WBGENE00011396
caenorhabditis_elegans		WBGENE00011520
caenorhabditis_elegans		WBGENE00011565
caenorhabditis_elegans		WBGENE00011566
caenorhabditis_elegans		WBGENE00011568
caenorhabditis_elegans	nhr-217	WBGENE00011651
caenorhabditis_elegans		WBGENE00011750
caenorhabditis_elegans		WBGENE00012050
caenorhabditis_elegans		WBGENE00012056
caenorhabditis_elegans		WBGENE00012446
caenorhabditis_elegans		WBGENE00012449
caenorhabditis_elegans		WBGENE00012596
caenorhabditis_elegans		WBGENE00012703
caenorhabditis_elegans		WBGENE00013067
caenorhabditis_elegans		WBGENE00013483
caenorhabditis_elegans	nhr-276	WBGENE00013512
caenorhabditis_elegans		WBGENE00013584
caenorhabditis_elegans		WBGENE00013940
caenorhabditis_elegans		WBGENE00014068
caenorhabditis_elegans	nhr-245	WBGENE00014189
caenorhabditis_elegans		WBGENE00014193
caenorhabditis_elegans		WBGENE00015497
caenorhabditis_elegans		WBGENE00015758
caenorhabditis_elegans		WBGENE00015897
caenorhabditis_elegans		WBGENE00015900
caenorhabditis_elegans		WBGENE00015901
caenorhabditis_elegans		WBGENE00015902
caenorhabditis_elegans		WBGENE00016091
caenorhabditis_elegans		WBGENE00016233
caenorhabditis_elegans		WBGENE00016364
caenorhabditis_elegans		WBGENE00016365
caenorhabditis_elegans		WBGENE00016366
caenorhabditis_elegans		WBGENE00016367
caenorhabditis_elegans		WBGENE00016368
caenorhabditis_elegans		WBGENE00016517
caenorhabditis_elegans		WBGENE00016772
caenorhabditis_elegans		WBGENE00016926
caenorhabditis_elegans		WBGENE00016927
caenorhabditis_elegans		WBGENE00017503
caenorhabditis_elegans		WBGENE00017512
caenorhabditis_elegans		WBGENE00017961
caenorhabditis_elegans		WBGENE00018189
caenorhabditis_elegans		WBGENE00018265
caenorhabditis_elegans		WBGENE00018266
caenorhabditis_elegans		WBGENE00018404
caenorhabditis_elegans		WBGENE00018412
caenorhabditis_elegans		WBGENE00018415
caenorhabditis_elegans		WBGENE00018539
caenorhabditis_elegans		WBGENE00018541
caenorhabditis_elegans		WBGENE00018542
caenorhabditis_elegans		WBGENE00018544
caenorhabditis_elegans		WBGENE00018545
caenorhabditis_elegans		WBGENE00018622
caenorhabditis_elegans		WBGENE00019115
caenorhabditis_elegans		WBGENE00019116
caenorhabditis_elegans		WBGENE00019741
caenorhabditis_elegans		WBGENE00019742
caenorhabditis_elegans		WBGENE00019743
caenorhabditis_elegans		WBGENE00020015
caenorhabditis_elegans		WBGENE00020062
caenorhabditis_elegans		WBGENE00020152
caenorhabditis_elegans		WBGENE00020153
caenorhabditis_elegans		WBGENE00020385
caenorhabditis_elegans		WBGENE00020460
caenorhabditis_elegans		WBGENE00020555
caenorhabditis_elegans		WBGENE00020750
caenorhabditis_elegans		WBGENE00020849
caenorhabditis_elegans		WBGENE00020850
caenorhabditis_elegans		WBGENE00020851
caenorhabditis_elegans		WBGENE00020852
caenorhabditis_elegans		WBGENE00021163
caenorhabditis_elegans		WBGENE00021522
caenorhabditis_elegans		WBGENE00021610
caenorhabditis_elegans		WBGENE00021611
caenorhabditis_elegans		WBGENE00021617
caenorhabditis_elegans		WBGENE00022097
caenorhabditis_elegans		WBGENE00022637
caenorhabditis_elegans		WBGENE00022639
caenorhabditis_elegans		WBGENE00022640
caenorhabditis_elegans		WBGENE00022726
caenorhabditis_elegans		WBGENE00022756
caenorhabditis_elegans		WBGENE00022805
caenorhabditis_elegans		WBGENE00044353
caenorhabditis_elegans		WBGENE00044699
caenorhabditis_elegans		WBGENE00045515

Paralogs (18): NR1H4 (ENSG00000012504), NR1H3 (ENSG00000025434), RORA (ENSG00000069667), RARB (ENSG00000077092), VDR (ENSG00000111424), PPARD (ENSG00000112033), THRA (ENSG00000126351), NR1D1 (ENSG00000126368), NR1H2 (ENSG00000131408), RARA (ENSG00000131759), PPARG (ENSG00000132170), NR1I3 (ENSG00000143257), RORC (ENSG00000143365), NR1I2 (ENSG00000144852), RARG (ENSG00000172819), NR1D2 (ENSG00000174738), PPARA (ENSG00000186951), RORB (ENSG00000198963)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:98743) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 106 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased circulating thyroxine level	12
increased circulating thyroid-stimulating hormone level	9
increased circulating triiodothyronine level	9
increased or absent threshold for auditory brainstem response	7
abnormal cochlear inner hair cell physiology	5
enlarged tectorial membrane	4
enlarged thyroid gland	4
short tibia	3
premature endochondral bone ossification	3
thyroid gland hyperplasia	3
increased activity of thyroid gland	3
abnormal response/metabolism to endogenous compounds	3
abnormal thyroid follicle morphology	3
increased thyroxine level	3
abnormal cochlea morphology	2
abnormal organ of Corti morphology	2
premature cranial suture closure	2
abnormal retina cone cell morphology	2
decreased body weight	2
decreased body size	2
postnatal growth retardation	2
deafness	2
abnormal bone mineralization	2
abnormal tectorial membrane morphology	2
premature intramembranous bone ossification	2

+81 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
Gallus gallus	P04625	100.0%	Diamond
Cairina moschata	P68305	100.0%	Diamond
Coturnix japonica	Q9W6B3	99.8%	Diamond
Cricetulus griseus	P57797	99.6%	Diamond
Xenopus laevis	P15204	99.5%	Diamond
Canis lupus familiaris	Q5FBR4	99.4%	Diamond
Aptenodytes patagonicus	O42295	99.3%	Diamond
Macaca mulatta	O18924	99.2%	Diamond
Pan troglodytes	A2T7D9	98.9%	Diamond
Pygoscelis adeliae	O42450	98.8%	Diamond
Pongo abelii	Q5RCZ5	98.8%	Diamond
Macaca fascicularis	Q95K90	98.8%	Diamond
Oncorhynchus mykiss	Q9W6I9	98.6%	Diamond
Salmo salar	Q9W785	98.6%	Diamond
Sus scrofa	O97716	98.3%	Diamond
Oryctolagus cuniculus	O19052	98.1%	Diamond
Aquarana catesbeiana	Q02777	98.1%	Diamond
Ovis aries	Q28570	98.1%	Diamond
Bos taurus	Q04752	97.6%	Diamond
Eleutherodactylus coqui	Q9PUA8	97.2%	Diamond
Paralichthys olivaceus	Q91241	97.1%	Diamond
Hippoglossus hippoglossus	Q9W6N4	97.1%	Diamond
Equus caballus	Q9GKL2	96.5%	Diamond
Pusa sibirica	P62045	95.4%	Diamond
Necturus maculosus	O57606	94.4%	Diamond
Sparus aurata	O57568	93.8%	Diamond
Notophthalmus viridescens	P18516	92.9%	Diamond
Takifugu rubripes	Q9W5Z3	92.5%	Diamond
Xenopus tropicalis	A4IIG7	91.3%	Diamond
Manduca sexta	Q08893	90.9%	Diamond
Heliothis virescens	O18473	88.2%	Diamond
Drosophila virilis	Q24753	88.2%	Diamond
Lucilia cuprina	O18531	81.1%	Diamond
Aedes aegypti	P49880	80.7%	Diamond
Avian erythroblastosis virus (strain ES4)	P03373	96.6%	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
THRB-AS1	ncRNA	644990
THRB-AS2	ncRNA	101927854
LINC00691	ncRNA	152024
NKIRAS1	protein-coding	28512
NR1D2	protein-coding	9975

Protein

Protein identifiers

Thyroid hormone receptor beta — P10828 (reviewed: P10828)

Alternative names: Nuclear receptor subfamily 1 group A member 2, c-erbA-2, c-erbA-beta

All UniProt accessions (10): P10828, A0A024R2I8, A0A0C4DG57, A0A2R8YF24, C9JHC2, C9JJM3, C9JNQ4, C9JTN1, C9JZS5, J3KR21

UniProt curated annotations — full annotation on UniProt →

Function. Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine.

Subunit / interactions. Binds DNA as a dimer; homodimer and heterodimer with RXRA. Interacts with the coactivators NCOA1/SRC1, NCOA2/GRIP1, NCOA7 and MED1/TRAP220 in a ligand-inducible manner. Interacts with the corepressor NCOR1 in absence of ligand. Interacts with C1D. Interacts with NR2F6; the interaction impairs the binding of the THRB homodimer and THRB:RXRB heterodimer to T3 response elements. Interacts with PRMT2 and THRSP. Interacts with TACC1; this interaction is decreased in the presence of thyroid hormone T3.

Subcellular location. Nucleus.

Disease relevance. Thyroid hormone resistance, generalized, autosomal dominant (GRTHD) [MIM:188570] An autosomal dominant disease characterized by high levels of circulating thyroid hormones (T3-T4), goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. Patients have normal or slightly elevated thyroid stimulating hormone (TSH). The disease is caused by variants affecting the gene represented in this entry. Thyroid hormone resistance, generalized, autosomal recessive (GRTHR) [MIM:274300] An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone. The disease is caused by variants affecting the gene represented in this entry. Selective pituitary thyroid hormone resistance (PRTH) [MIM:145650] Variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.

Similarity. Belongs to the nuclear hormone receptor family. NR1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P10828-1	Beta-1	yes
P10828-2	Beta-2

RefSeq proteins (18): NP_000452, NP_001121648, NP_001121649, NP_001239563, NP_001341637, NP_001341638, NP_001341639, NP_001341640, NP_001341641, NP_001341642, NP_001341643, NP_001341644, NP_001361751, NP_001361752, NP_001361753, NP_001361754, NP_001361755, NP_001361756 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR001728	ThyrH_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR050234	Nuclear_hormone_rcpt_NR1	Family

Pfam: PF00104, PF00105

UniProt features (101 total): sequence variant 36, helix 23, binding site 14, strand 7, turn 6, mutagenesis site 5, zinc finger region 2, region of interest 2, sequence conflict 2, chain 1, domain 1, DNA-binding region 1, splice variant 1

Structure

Experimental structures (PDB)

showing 30 of 34 structures by resolution:

PDB	Title	Method	Resolution (Å)
6KKB	A novel agonist of THRb	X-RAY DIFFRACTION	1.7
2NLL	RETINOID X RECEPTOR-THYROID HORMONE RECEPTOR DNA-BINDING DOMAIN HETERODIMER BOUND TO …	X-RAY DIFFRACTION	1.9
7WMH	A novel chemical derivative(56) of THRB agonist	X-RAY DIFFRACTION	1.97
1N46	CRYSTAL STRUCTURE OF HUMAN TR BETA LIGAND-BINDING DOMAIN COMPLEXED WITH A POTENT …	X-RAY DIFFRACTION	2.2
2J4A	Human Thyroid hormone receptor beta ligand binding domain in complex with KB131084	X-RAY DIFFRACTION	2.2
3D57	TR Variant D355R	X-RAY DIFFRACTION	2.2
3GWS	Crystal Structure of T3-Bound Thyroid Hormone Receptor	X-RAY DIFFRACTION	2.2
2PIN	Thyroid receptor beta in complex with inhibitor	X-RAY DIFFRACTION	2.3
7WLX	A novel chemical derivative(53) of THRB agonist	X-RAY DIFFRACTION	2.39
1NQ0	TR Receptor Mutations Conferring Hormone Resistance and Reduced Corepressor Release …	X-RAY DIFFRACTION	2.4
1NQ2	Two RTH Mutants with Impaired Hormone Binding	X-RAY DIFFRACTION	2.4
1XZX	Thyroxine-Thyroid Hormone Receptor Interactions	X-RAY DIFFRACTION	2.5
3JZC	Crystal Structure of TR-beta bound to the selective thyromimetic TRIAC	X-RAY DIFFRACTION	2.5
3IMY	Structure of TR-beta bound to selective thyromimetic GC-1	X-RAY DIFFRACTION	2.55
7WMO	A novel chemical derivative(92) of THRB agonist	X-RAY DIFFRACTION	2.56
7WMN	A novel chemical derivative(89) of THRB agonist	X-RAY DIFFRACTION	2.57
6KKE	THRb mutation with a novel agonist	X-RAY DIFFRACTION	2.58
9IX5	An agonist(compound 15n) of Thyroid Hormone Receptor B	X-RAY DIFFRACTION	2.65
6KNW	THRb mutation with a novel agonist	X-RAY DIFFRACTION	2.67
7WML	A novel chemical derivative(85) of THRB agonist	X-RAY DIFFRACTION	2.67
9J0K	An agonist(compound 14e)of Thyroid Hormone Receptor B	X-RAY DIFFRACTION	2.7
1NAX	Thyroid receptor beta1 in complex with a beta-selective ligand	X-RAY DIFFRACTION	2.7
6KNU	THRb mutation with a novel agonist	X-RAY DIFFRACTION	2.7
1Q4X	Crystal Structure of Human Thyroid Hormone Receptor beta LBD in complex with specific …	X-RAY DIFFRACTION	2.8
6KNV	THRb mutation with a novel agonist	X-RAY DIFFRACTION	2.8
7WMJ	A novel chemical derivative(71) of THRB agonist	X-RAY DIFFRACTION	2.81
8RQN	Human thyroid hormone receptor beta ligand binding domain in complex with beta-selective …	X-RAY DIFFRACTION	2.88
1NQ1	TR Receptor Mutations Conferring Hormone Resistance and Reduced Corepressor Release …	X-RAY DIFFRACTION	2.9
7WMG	A novel chemical derivative(52) of THRB agonist	X-RAY DIFFRACTION	2.93
1R6G	Crystal structure of the thyroid hormone receptor beta ligand binding domain in complex …	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10828-F1	80.24	0.69

Human Protein Atlas

Protein class: Nuclear receptors, Predicted intracellular proteins, Transcription factors, Zinc-coordinating DNA-binding domains, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear bodies

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

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

Ligand- & substrate-binding residues (14)

Position	Role
127	Zn(2+)
145	Zn(2+)
151	Zn(2+)
161	Zn(2+)
164	Zn(2+)
282	3,3’,5-triiodo-L-thyronine
282	L-thyroxine
331	3,3’,5-triiodo-L-thyronine
331	L-thyroxine
435	3,3’,5-triiodo-L-thyronine
435	L-thyroxine
107	Zn(2+)
110	Zn(2+)
124	Zn(2+)

Mutagenesis-validated functional residues (5)

Position	Phenotype
207–208	modestly inhibits homodimer formation on a minimal response element (in vitro).
207–208	inhibits homodimer formation on a minimal response element (in vitro).
243	impairs hormone binding and ligand-dependent conformational changes.
331	no effect on thyroid hormone binding.
355	stabilizes homodimer.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 9; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

9 pathways:

ID	Pathway	Evidence
R-HSA-383280	Nuclear Receptor transcription pathway	curated
R-HSA-4090294	SUMOylation of intracellular receptors	curated
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins	—
R-HSA-2990846	SUMOylation	—

MSigDB gene sets: 338 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, TAATAAT_MIR126, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GGTGTGT_MIR329, GOBP_BEHAVIOR, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_LUNG_CELL_DIFFERENTIATION, AAGCCAT_MIR135A_MIR135B, CACCAGC_MIR138, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, CHANG_IMMORTALIZED_BY_HPV31_DN, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), thyroid hormone receptor signaling pathway (GO:0002154), positive regulation of thyroid hormone receptor signaling pathway (GO:0002157), DNA-templated transcription (GO:0006351), cell differentiation (GO:0030154), mRNA transcription by RNA polymerase II (GO:0042789), positive regulation of transcription by RNA polymerase II (GO:0045944), retinoic acid receptor signaling pathway (GO:0048384), cellular response to thyroid hormone stimulus (GO:0097067), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), intracellular receptor signaling pathway (GO:0030522)

GO Molecular Function (15): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coactivator binding (GO:0001223), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), nuclear receptor activity (GO:0004879), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), chromatin DNA binding (GO:0031490), thyroid hormone binding (GO:0070324), sequence-specific double-stranded DNA binding (GO:1990837), chromatin binding (GO:0003682), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

7 top-level categories:

Category	Pathways
Generic Transcription Pathway	1
SUMO E3 ligases SUMOylate target proteins	1
RNA Polymerase II Transcription	1
Post-translational protein modification	1
SUMOylation	1
Metabolism of proteins	1
Gene expression (Transcription)	1

GO top-level categories

49 GO namespaces:

Category	Terms
transcription by RNA polymerase II	4
regulation of transcription by RNA polymerase II	3
hormone-mediated signaling pathway	2
nuclear receptor-mediated signaling pathway	2
regulation of DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA binding	2
binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
thyroid hormone receptor signaling pathway	1
regulation of thyroid hormone receptor signaling pathway	1
positive regulation of intracellular signal transduction	1
gene expression	1
RNA biosynthetic process	1
cellular developmental process	1
mRNA transcription	1
positive regulation of DNA-templated transcription	1
cellular response to hormone stimulus	1
response to thyroid hormone	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
intracellular signal transduction	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription coregulator binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
intracellular receptor signaling pathway	1
signaling receptor activity	1
ligand-modulated transcription factor activity	1
transition metal ion binding	1
protein binding	1
chromatin binding	1
hormone binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nucleoplasm	1
intracellular membraneless organelle	1
transcription regulator complex	1
nuclear protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 32 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
cellular response to thyroid hormone stimulus	BP	direct assay
mRNA transcription by RNA polymerase II	BP	direct assay
positive regulation of thyroid hormone receptor signaling pathway	BP	direct assay
positive regulation of transcription by RNA polymerase II	BP	direct assay
nuclear body	CC	direct assay
enzyme binding	MF	physical interaction
nuclear receptor activity	MF	direct assay
sequence-specific double-stranded DNA binding	MF	direct assay
thyroid hormone binding	MF	direct assay
transcription coactivator binding	MF	physical interaction

Protein interactions and networks

STRING

showing 16 of 1,518 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THRB	TXNRD2	Q9NNW7	950
THRB	DIO2	Q92813	772
THRB	TRH	P20396	732
THRB	TSHR	P16473	697
THRB	DIO3	P55073	676
THRB	SLC16A2	P36021	674
THRB	TRIP13	Q15645	637
THRB	TSHB	P01222	619
THRB	TRIP4	Q15650	604
THRB	DIO1	P49895	602
THRB	ZNHIT3	Q15649	601
THRB	SERPINA7	P05543	578
THRB	XPR1	Q9UBH6	571
THRB	ME1	P48163	571
THRB	NCOA7	Q8NI08	566
THRB	NCOA1	Q15788	566

IntAct

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

16 partners by confidence:

Partner	Interaction type	MIscore	Records
ACTB	association	0.530	1
PIK3R1	direct interaction	0.440	1
RXRA	direct interaction	0.440	1
EIF5B	physical association	0.400	1
PRMT2	physical association	0.400	1
NCOA6	physical association	0.370	2
ADAT3	physical association	0.370	1
CCL1	physical association	0.370	1
CCL22	physical association	0.370	1
CNOT1	physical association	0.370	1
IFNL1	physical association	0.370	1
IL25	physical association	0.370	1
IL31	physical association	0.370	1
MED25	physical association	0.370	1
NRAS	association	0.350	1
FMR1	physical association	0.000	1

BioGRID (124 interactions; top human partners by supporting records): NCOA1 (Reconstituted Complex; 10 records), NCOR1 (Reconstituted Complex; 9 records), RXRA (Reconstituted Complex; 9 records), NCOR2 (Reconstituted Complex; 6 records), NCOA2 (Reconstituted Complex; 4 records), NCOA6 (Reconstituted Complex; 4 records), RANBP9 (Two-hybrid; 4 records), NCOA3 (Two-hybrid; 3 records), NR2F6 (Reconstituted Complex; 3 records), PSMC5 (Two-hybrid; 3 records), TP53 (Reconstituted Complex; 3 records), ACTA2 (Affinity Capture-MS; 2 records), ACTB (Affinity Capture-MS; 2 records), ACTBL2 (Affinity Capture-MS; 2 records), BRD8 (Two-hybrid; 2 records)

SIGNOR signaling

13 signaling interactions:

A	Effect	B	Mechanism
MAPK1	“down-regulates activity”	THRB	phosphorylation
MAPK3	“down-regulates activity”	THRB	phosphorylation
D-thyroxine	“up-regulates activity”	THRB	“chemical activation”
ASXL3	“down-regulates activity”	THRB	binding
3,3’,5’-triiodothyronine	“up-regulates activity”	THRB	binding
THRB	“down-regulates activity”	GATA2	binding
Gbeta	“down-regulates activity”	THRB	phosphorylation
ERK1/2	“down-regulates activity”	THRB	phosphorylation
TRIP11	up-regulates	THRB	binding
RXRA	up-regulates	THRB	binding
RXRB	up-regulates	THRB	binding
L-thyroxine	“up-regulates activity”	THRB	“chemical activation”
3,3’,5’-triiodothyronine	“up-regulates activity”	THRB	“chemical activation”

Protein complexes (CORUM) (18)

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

18 complexes by size:

Complex	Subunits	Members
★ NCOR2-RXRA-THRB complex	3	NCOR2, RXRA, THRB
★ NCOR2-THRB-TRIP4 complex	3	NCOR2, THRB, TRIP4
★ RXRB-THRB complex	2	RXRB, THRB
★ RXRA-THRB complex	2	RXRA, THRB
★ NCOR2-THRB complex	2	NCOR2, THRB
★ ANP32A-THRB complex	2	ANP32A, THRB
★ THRB-TRIP4 complex	2	THRB, TRIP4
★ MED1-THRB complex	2	MED1, THRB
★ NR0B2-THRB complex	2	NR0B2, THRB
★ NCOA6-THRB complex	2	NCOA6, THRB
★ NCOA7-THRB complex	2	NCOA7, THRB
★ PRMT2-THRB complex	2	THRB, PRMT2
★ FOXO1-THRB complex	2	FOXO1, THRB
★ NCOA3-THRB complex	2	NCOA3, THRB
★ NRIP1-THRB complex	2	NRIP1, THRB
★ COPS2-THRB complex	2	COPS2, THRB
★ NFKBIB-THRB complex	2	THRB, NFKBIB
★ PPARGC1A-THRB complex	2	PPARGC1A, THRB

Ligand–receptor pairs (CellPhoneDB) (2)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

2 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
TPO	receptor
DIO3;TG	receptor	Signaling by Triiodothyronine

Disease & clinical

Genetic variants

Variant evidence for THRB: 756 ClinVar records (81 pathogenic / likely pathogenic); 80 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	47
Likely pathogenic	34
Uncertain significance	393
Likely benign	132
Benign	80

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 81 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
12542	NM_001354712.2(THRB):c.949G>A (p.Ala317Thr)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
12550	NM_001354712.2(THRB):c.1357C>A (p.Pro453Thr)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
12559	NM_001354712.2(THRB):c.1313G>A (p.Arg438His)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
12557	NM_001354712.2(THRB):c.958C>T (p.Arg320Cys)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
12558	NM_001354712.2(THRB):c.1012C>T (p.Arg338Trp)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
439310	NM_001354712.2(THRB):c.1357C>T (p.Pro453Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
12555	NM_001354712.2(THRB):c.947G>A (p.Arg316His)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
12552	NM_001354712.2(THRB):c.1033G>A (p.Gly345Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
437004	NM_001354712.2(THRB):c.1305T>G (p.His435Gln)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
492915	NM_001354712.2(THRB):c.938T>C (p.Met313Thr)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
492925	NM_001354712.2(THRB):c.1358dup (p.Leu454fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
38366	NM_002769.5(PRSS1):c.86A>C (p.Asn29Thr)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1338370	NM_001354712.2(THRB):c.830C>T (p.Thr277Ile)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
12564	NM_001354712.2(THRB):c.1373T>C (p.Val458Ala)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	6
12547	NM_001354712.2(THRB):c.1324A>G (p.Met442Val)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5

Per-variant reference — Sugi Variant

Explore THRB’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 40 predictions of 2,438):

Position(s)	Effect	Δscore	Sites
3:24127497–24127498	donor_loss	1.0000	4
3:24133463–24133464	acceptor_loss	1.0000	6
3:24143499–24143500	donor_loss	1.0000	5
3:24143707–24143708	acceptor_loss	1.0000	5
3:24127497	donor_loss	0.9900
3:24127758–24127759	acceptor_loss	0.9900	6
3:24127780	acceptor_gain	0.9900
3:24133314–24133315	donor_loss	0.9900	5
3:24143707	acceptor_loss	0.9900
3:24152388–24152389	donor_loss	0.9900	6

AlphaMissense

1,735 missense substitutions predicted likely pathogenic (of 3,073 scored), across 320 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
M174	9	0.999	1.000
M313	9	0.962	1.000
M310	9	0.960	0.998
M423	9	0.928	0.997
M442	9	0.897	0.996
H118	8	1.000	1.000
D112	8	0.999	1.000
F130	8	0.998	1.000
F131	8	0.998	1.000
N159	8	0.998	1.000
N195	8	0.996	0.999
D300	8	0.996	0.999
H435	8	0.996	0.999
F459	8	0.995	1.000
F286	8	0.993	1.000
F293	8	0.993	1.000
F354	8	0.991	1.000
F269	8	0.989	0.999
H229	8	0.988	0.999
F455	8	0.988	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.53e-10
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000586
Stomach Adenocarcinoma (TCGA)	unfavorable	0.000753

Disease associations

OMIM: gene MIM:190160 | disease phenotypes: MIM:167800, MIM:188570, MIM:274300, MIM:145650

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
thyroid hormone resistance, generalized, autosomal dominant	Strong	Autosomal dominant	2
resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta	Supportive	Autosomal recessive
thyroid hormone resistance, generalized, autosomal recessive	Limited	Autosomal recessive

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (7 panels, 3 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

7 panels:

Panel	Rating
Congenital hypothyroidism	green
Hyperthyroidism	green
Retinal disorders	green
Hypotonic infant	amber
Intellectual disability	amber
Leukodystrophy, childhood onset	amber
Paediatric disorders	amber

Mondo (10): hereditary chronic pancreatitis (MONDO:0008185), thyroid hormone resistance, generalized, autosomal dominant (MONDO:0008569), thyroid hormone resistance, generalized, autosomal recessive (MONDO:0010131), generalized resistance to thyroid hormone (MONDO:0009043), thyroid hormone resistance syndrome (MONDO:0001328), hyperthyroidism (MONDO:0004425), selective pituitary resistance to thyroid hormone (MONDO:0007784), neurodevelopmental disorder (MONDO:0700092), resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta (MONDO:0700478), (MONDO:0034217)

Orphanet (5): Autosomal dominant hereditary chronic pancreatitis (Orphanet:676), Syndrome of reduced sensitivity to thyroid hormone (Orphanet:596426), Resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta (Orphanet:566243), Generalized resistance to thyroid hormone (Orphanet:3221), Pituitary resistance to thyroid hormone (Orphanet:165994)

HPO phenotypes

39 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000403	Recurrent otitis media
HP:0000407	Sensorineural hearing impairment
HP:0000520	Proptosis
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000819	Diabetes mellitus
HP:0000836	Hyperthyroidism
HP:0000853	Goiter
HP:0001328	Specific learning disability
HP:0001518	Small for gestational age
HP:0001530	Mild postnatal growth retardation
HP:0001649	Tachycardia
HP:0001962	Palpitations
HP:0002750	Delayed skeletal maturation
HP:0002925	Elevated circulating thyroid-stimulating hormone concentration
HP:0002930	Impaired sensitivity to thyroid hormone
HP:0003621	Juvenile onset
HP:0004324	Increased body weight
HP:0005978	Type II diabetes mellitus
HP:0007018	Attention deficit hyperactivity disorder
HP:0008223	Compensated hypothyroidism
HP:0010655	Epiphyseal stippling
HP:0011463	Childhood onset
HP:0011788	Increased circulating free T3
HP:0012378	Fatigue
HP:0012758	Neurodevelopmental delay
HP:0025379	Anti-thyroid peroxidase antibody positivity
HP:0025484	Elevated circulating thyroglobulin concentration
HP:0031098	Decreased thyroid-stimulating hormone level
HP:0031506	Increased circulating T4 concentration
HP:0032069	Anti-thyroglobulin antibody positivity
HP:0033075	Inappropriately normal thyroid-stimulating hormone level
HP:0033077	Increased circulating free T4 concentration
HP:0034189	Anti-thyroid-stimulating hormone receptor antibody positivity
HP:0034288	Elevated circulating reverse T3 concentration

GWAS associations

showing 30 of 80 associations:

Study	Trait	p-value
GCST90002392_314	Mean corpuscular volume	2e-178
GCST90002390_583	Mean corpuscular hemoglobin	2e-175
GCST004630_44	Mean corpuscular hemoglobin	7e-77
GCST004602_77	Mean corpuscular volume	6e-75
GCST90002403_436	Red blood cell count	3e-61
GCST90002406_236	Reticulocyte fraction of red cells	8e-49
GCST90002397_705	Mean spheric corpuscular volume	3e-48
GCST90002396_19	Mean reticulocyte volume	7e-48
GCST90002386_275	High light scatter reticulocyte percentage of red cells	4e-45
GCST010002_417	Refractive error	4e-34
GCST006011_99	Mean corpuscular volume	8e-31
GCST004601_134	Red blood cell count	2e-30
GCST90002385_562	High light scatter reticulocyte count	1e-29
GCST90002405_214	Reticulocyte count	2e-28
GCST010320_26	PR interval	4e-27
GCST010321_110	PR interval	9e-27
GCST005993_18	Mean corpuscular hemoglobin	5e-23
GCST90002404_467	Red cell distribution width	3e-22
GCST004612_66	High light scatter reticulocyte percentage of red cells	6e-18
GCST004619_209	Reticulocyte fraction of red cells	1e-17
GCST90002393_420	Monocyte count	9e-17
GCST001765_20	Red blood cell traits	6e-16
GCST90002394_497	Monocyte percentage of white cells	3e-15
GCST90002387_242	Immature fraction of reticulocytes	7e-15
GCST004621_136	Red cell distribution width	4e-14
GCST90002388_422	Lymphocyte count	2e-13
GCST90002391_32	Mean corpuscular hemoglobin concentration	4e-13
GCST006979_29	Heel bone mineral density	6e-13
GCST90002405_213	Reticulocyte count	8e-13
GCST002541_71	Menarche (age at onset)	2e-12

EFO canonical traits (from GWAS)

31 canonical traits:

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0006335	systolic blood pressure
EFO:0004703	age at menarche
EFO:0007792	antipsychotic drug use measurement
EFO:0004305	erythrocyte count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0005091	monocyte count
EFO:0006953	family history of lung cancer
EFO:0004847	age at onset
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004747	protein measurement
EFO:0005188	CCL11 measurement
EFO:0005939	parental genotype effect measurement
EFO:0007964	gestational serum measurement
EFO:0009270	heel bone mineral density
EFO:0004337	intelligence
EFO:0008328	chronotype measurement
EFO:0005405	response to antihypertensive drug
EFO:0006527	smoking status measurement
EFO:0004530	triglyceride measurement
EFO:0004462	PR interval
EFO:0007874	gut microbiome measurement
EFO:0004327	electrocardiography
EFO:0004980	appendicular lean mass
EFO:0004587	lymphocyte count
EFO:0007989	monocyte percentage of leukocytes
EFO:0010701	mean reticulocyte volume
EFO:0007984	platelet component distribution width

MeSH disease descriptors

7 disease descriptors:

Descriptor	Name	Tree numbers
D006980	Hyperthyroidism	C19.874.397
D065886	Neurodevelopmental Disorders	F03.625
D018382	Thyroid Hormone Resistance Syndrome	C19.874.410.500
C537262	Hereditary pancreatitis *(supp.)*
C567934	Thyroid Hormone Resistance, Generalized, Autosomal Dominant *(supp.)*
C567936	Thyroid Hormone Resistance, Generalized, Autosomal Recessive *(supp.)*
C564154	Thyroid Hormone Resistance, Selective Pituitary *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1947 (SINGLE PROTEIN), CHEMBL2111462 (PROTEIN COMPLEX)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the THRB 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.

3 curated-mechanism drugs:

Drug	Modality	Max phase
RESMETIROM	Small molecule	4
EPROTIROME	Small molecule	3
MB07811	Small molecule	2

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 THRB — the drug acts on the assembly or class, not necessarily on this subunit alone.

4 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
DEXTROTHYROXINE	Thyroid hormone receptor	2	4
LEVOTHYROXINE SODIUM	Thyroid hormone receptor	2	4
LIOTHYRONINE	Thyroid hormone receptor	2	4
TIRATRICOL	Thyroid hormone receptor	2	3

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 569,006 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

showing 60 of 117 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL3261331	RESMETIROM	4	1,380
CHEMBL20	ACETAZOLAMIDE	4	29,000
CHEMBL1589	ACETOHEXAMIDE	4	18,443
CHEMBL600	ACETYLCYSTEINE	4	96,284
CHEMBL1455	ALTRETAMINE	4	103,108
CHEMBL1569	AMANTADINE HYDROCHLORIDE	4	11,279
CHEMBL1398126	AMILORIDE HYDROCHLORIDE	4	2,113
CHEMBL1046	AMINOCAPROIC ACID	4	96,126
CHEMBL288470	AMINOPYRINE	4	8,309
CHEMBL633	AMIODARONE	4	30,023
CHEMBL1113	AMOXAPINE	4	20,303
CHEMBL1487	ATORVASTATIN	4	69,270
CHEMBL515914	AZARIBINE	4	3,119
CHEMBL388590	BENZBROMARONE	4	8,286
CHEMBL1472989	BISOPROLOL FUMARATE	4	10,113
CHEMBL290106	BITHIONOL	4	6,490
CHEMBL73234	CARBETAPENTANE	4	7,334
CHEMBL110691	CHLORMADINONE ACETATE	4	9,833
CHEMBL1200714	CHLORMEZANONE	4	2,128
CHEMBL498	CHLORPROPAMIDE	4	36,065
CHEMBL1200710	CLOMIPRAMINE HYDROCHLORIDE	4
CHEMBL61593	CYCLOTHIAZIDE	4
CHEMBL803	CYTARABINE	4
CHEMBL178	DAUNORUBICIN	4
CHEMBL1563	DAUNORUBICIN HYDROCHLORIDE	4
CHEMBL1593558	DEBRISOQUIN SULFATE	4
CHEMBL559	DEXTROTHYROXINE	4
CHEMBL181	DIAZOXIDE	4
CHEMBL1697	DILTIAZEM HYDROCHLORIDE	4
CHEMBL932	DIPYRIDAMOLE	4
CHEMBL517	DISOPYRAMIDE	4
CHEMBL421701	DITHIAZANINE IODIDE	4
CHEMBL359744	DOXORUBICIN HYDROCHLORIDE	4
CHEMBL1201217	DYCLONINE	4
CHEMBL1200478	DYCLONINE HYDROCHLORIDE	4
CHEMBL64894	GENTIAN VIOLET	4
CHEMBL496	HEXACHLOROPHENE	4
CHEMBL435	HYDROCHLOROTHIAZIDE	4
CHEMBL1117	IDARUBICIN	4
CHEMBL12856	INAMRINONE	4
CHEMBL1091250	INDIGOTINDISULFONATE	4
CHEMBL1200660	ISOSORBIDE	4
CHEMBL547	ISOTRETINOIN	4
CHEMBL960	LEFLUNOMIDE	4
CHEMBL1624	LEVOTHYROXINE	4
CHEMBL1544	LIOTHYRONINE	4
CHEMBL1201119	LIOTHYRONINE SODIUM	4
CHEMBL1562610	MECLOFENAMATE SODIUM	4
CHEMBL704	MESALAMINE	4
CHEMBL2146123	METHACYCLINE HYDROCHLORIDE	4
CHEMBL550495	METHYLENE BLUE	4
CHEMBL405110	METHYLENE BLUE ANHYDROUS	4
CHEMBL191083	METHYLENE BLUE CATION	4
CHEMBL1200938	METHYSERGIDE MALEATE	4
CHEMBL137	METRONIDAZOLE	4
CHEMBL1329455	MOLSIDOMINE	4
CHEMBL1517	OXYTETRACYCLINE	4
CHEMBL428647	PACLITAXEL	4
CHEMBL1200787	PHENOXYBENZAMINE HYDROCHLORIDE	4
CHEMBL1611	PHENYTOIN SODIUM	4

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

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

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs892940	salbutamol	Efficacy	Allele A is associated with increased bronchodilator response (BDR) when treated with salbutamol in children with Asthma as compared to allele G.	PMID:22212731

GtoPdb / IUPHAR curated pharmacology

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

Target class: nhr — 1A. Thyroid hormone receptors

Most potent curated ligand interactions (10 total), top 10:

Ligand	Action	Affinity	Parameter
tiratricol	Agonist	10.7	pKd
sobetirome	Agonist	10.17	pKd
triiodothyronine	Agonist	10.1	pKd
KB-141	Agonist	8.96	pIC50
VK2809	Agonist	8.53	pKi
T4	Agonist	8.52	pIC50
compound 16g [PMID: 35507418]	Agonist	7.68	pEC50
rT3	Agonist	7.34	pKd
NH-3	Antagonist	7.03	pKd
resmetirom	Agonist	6.68	pEC50

Binding affinities (BindingDB)

788 measured of 995 human assays (1000 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[4-(4-HYDROXY-3-ISOPROPYL-PHENOXY)-3,5-DIMETHYL-PHENYL]-6-AZAURACIL	KI	0.03 nM
2-{3,5-Dichloro-4-[4-hydroxy-3-(piperidine-1-sulfonyl)-phenoxy]-phenyl}-2H-[1,2,4]triazine-3,5-dione	IC50	0.0562 nM
CHEMBL392666	EC50	0.06 nM
CHEMBL248111	EC50	0.08 nM
3-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}propanoic acid	IC50	0.1 nM
(2R)-2-amino-3-{4-[4-hydroxy-3-(propan-2-yl)phenoxy]-3,5-diiodophenyl}propanoic acid	IC50	0.14 nM
N-Cyclohexyl-5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-2-hydroxy-benzamide	IC50	0.195 nM
(S)-2-Amino-3-[4-(4-hydroxy-3-iodo-phenoxy)-3-iodo-5-methyl-phenyl]-propionic acid	EC50	0.2 nM
2-{3,5-Dichloro-4-[4-hydroxy-3-(indole-1-sulfonyl)-phenoxy]-phenyl}-2H-[1,2,4]triazine-3,5-dione	KI	0.23 nM
CHEMBL4761137	IC50	0.27 nM
5-(2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-2-hydroxy-N-phenylbenzenesulfonamide	IC50	0.282 nM
CHEMBL248515	EC50	0.3 nM
CHEMBL3397337	KI	0.35 nM
2-{3-Chloro-4-[4-hydroxy-3-(piperidine-1-sulfonyl)-phenoxy]-5-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione	IC50	0.363 nM
2-{4-[3-(2-Aza-bicyclo[2.2.1]heptane-2-carbonyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-2H-[1,2,4]triazine-3,5-dione	KI	0.37 nM
dibromo phenylacetic acid, 11a	EC50	0.38 nM
CHEMBL3397339	KI	0.38 nM
CHEMBL4749829	IC50	0.4 nM
2-[3,5-dibromo-4-(cyclohexylmethoxy)phenyl]acetic acid	EC50	0.42 nM
[4-(3-Isopropyl-1H-indol-5-yloxy)-3,5-bis-trifluoromethyl-phenyl]-acetic acid	EC50	0.5 nM
CHEMBL4754786	IC50	0.5 nM
N-[3,5-dimethyl-4-(4’-hydroxy-3’-isopropylphenoxy)phenyl]oxamic acid	KI	0.51 nM
CHEMBL3397341	KI	0.51 nM
JMC496635 Compound 9	EC50	0.53 nM
CHEMBL237096	IC50	0.646 nM
3-[4-(4-Hydroxy-3-isopropyl-benzyl)-3,5-dimethyl-phenyl]-propionic acid	KD	0.69 nM
2-[3,5-dibromo-4-(hexyloxy)phenyl]acetic acid	EC50	0.7 nM
2-(4-(7-hydroxy-2,3-dihydro-1H-inden-4-yloxy)-3,5-dimethylphenylamino)-2-oxoacetic acid	KI	0.7 nM
3-{3,5-dichloro-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}propanoic acid	IC50	0.759 nM
2-[3,5-dibromo-4-(2-ethylbutoxy)phenyl]acetic acid	EC50	0.82 nM
2-{3,5-dichloro-4-[4-hydroxy-3-spiro[8-azabicyclo[3.2.1]octane-3,2’-(dihydro[1,3]dioxolane)]-8-ylsulfonylphenoxy]phenyl}-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione	IC50	0.871 nM
CHEMBL237529	IC50	1.02 nM
CHEMBL3397336	KI	1.1 nM
D-Phe-Pro-p-amindinobenzylamine	KI	1.1 nM
N-cyclobutyl-5-(2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-2-hydroxybenzenesulfonamide	IC50	1.12 nM
N-[3,5-Dibromo-4-(3-isopropyl-1H-indol-5-yloxy)-phenyl]-oxalamic acid ethyl ester	EC50	1.2 nM
2-{4-[4-Hydroxy-3-(piperidine-1-sulfonyl)-phenoxy]-3,5-dimethyl-phenyl}-2H-[1,2,4]triazine-3,5-dione	IC50	1.29 nM
N-Cyclohexyl-5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-2-hydroxy-benzenesulfonamide	IC50	1.29 nM
(R)-2-Amino-3-[4-(4-hydroxy-3-iodo-phenoxy)-3,5-diiodo-phenyl]-propionic acid	EC50	1.3 nM
(2S)-2-(1-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}acetamido)-3-methylbutanoic acid	EC50	1.4 nM
[2-[[(1S)-1-(3-chlorophenyl)-2-fluoroethyl]amino]-7-methoxy-1,3-benzoxazol-5-yl]-[5-(3-hydroxycyclobutyl)-2-methylmorpholin-4-yl]methanone	IC50	1.4 nM	US-9493472: Substituted benzoxazoles
(2R)-2-(1-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}acetamido)-2-phenylacetic acid	EC50	1.5 nM
N-cyclobutyl-5-(2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-2-hydroxybenzamide	IC50	1.78 nM
3,5-Diiodo-4-(4’-hydroxy-3’-isopropylphenoxy)benzylphosphonicAcid	KI	1.84 nM
2-{3-Chloro-4-[4-hydroxy-3-(piperidine-1-carbonyl)-phenoxy]-5-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione	KI	1.9 nM
2-[3,5-Dimethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione	KI	2 nM
2-(3,5-dichloro-4-(4-hydroxy-3-(morpholine-4-carbonyl)phenoxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione	IC50	2 nM
CHEMBL4776051	IC50	2 nM
2-Amino-3-[4-(4-hydroxy-3-isopropyl-benzyl)-3,5-dimethyl-phenyl]-propionic acid	KD	2.02 nM
CHEMBL3397338	KI	2.1 nM

ChEMBL bioactivities

2838 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.72	IC50	0.019	nM	THYROPROPIC ACID
10.72	IC50	0.01905	nM	THYROPROPIC ACID
10.70	Ki	0.02	nM	CHEMBL124126
10.60	IC50	0.025	nM	CHEMBL289343
10.60	IC50	0.02512	nM	CHEMBL289343
10.52	Ki	0.03	nM	CHEMBL125381
10.40	Ki	0.04	nM	CHEMBL124205
10.40	Ki	0.04	nM	CHEMBL3397339
10.39	IC50	0.04074	nM	TIRATRICOL
10.32	IC50	0.048	nM	TIRATRICOL
10.32	IC50	0.04786	nM	TIRATRICOL
10.25	IC50	0.05623	nM	CHEMBL124126
10.22	Ki	0.06	nM	CHEMBL124205
10.22	Ki	0.06	nM	CHEMBL203777
10.22	IC50	0.06	nM	CHEMBL203777
10.22	EC50	0.06	nM	CHEMBL392666
10.22	IC50	0.06026	nM	CHEMBL203777
10.15	Ki	0.07	nM	CHEMBL413699
10.15	Ki	0.07	nM	CHEMBL3397337
10.10	Ki	0.08	nM	LIOTHYRONINE
10.10	EC50	0.08	nM	CHEMBL248111
10.09	Kd	0.081	nM	LIOTHYRONINE
10.06	Kd	0.087	nM	LIOTHYRONINE
10.05	Ki	0.09	nM	CHEMBL3397341
10.05	IC50	0.09	nM	CHEMBL4114879
10.02	IC50	0.095	nM	CHEMBL39174
10.02	IC50	0.0955	nM	CHEMBL39174
10.00	Ki	0.1	nM	CHEMBL126693
10.00	Kd	0.1	nM	SOBETIROME
10.00	Kd	0.1	nM	LIOTHYRONINE
9.99	IC50	0.103	nM	RATHYRONINE
9.96	IC50	0.11	nM	CHEMBL41314
9.96	IC50	0.1096	nM	CHEMBL235173
9.96	IC50	0.1096	nM	CHEMBL41314
9.95	IC50	0.1122	nM	CHEMBL124205
9.89	Ki	0.13	nM	CHEMBL125728
9.85	Ki	0.14	nM	CHEMBL3397338
9.85	Kd	0.14	nM	LIOTHYRONINE
9.82	IC50	0.15	nM	CHEMBL418432
9.82	IC50	0.1514	nM	CHEMBL418432
9.80	Ki	0.16	nM	CHEMBL338602
9.78	IC50	0.166	nM	CHEMBL124205
9.74	Ki	0.18	nM	CHEMBL3397340
9.71	IC50	0.195	nM	CHEMBL413699
9.70	EC50	0.2	nM	CHEMBL39174
9.70	Kd	0.2	nM	SOBETIROME
9.70	EC50	0.2	nM	CHEMBL182339
9.70	IC50	0.1995	nM	CHEMBL251456
9.66	Kd	0.22	nM	CHEMBL322361
9.64	Ki	0.23	nM	CHEMBL123920

PubChem BioAssay actives

947 with measured affinity, of 1605 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
3-[3,5-dibromo-4-(4-hydroxy-3-propan-2-ylphenoxy)phenyl]propanoic acid	1797784: TRbeta-Binding Assay from Article 10.1021/jm021080f: “Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.”	ic50	<0.0001	uM
2-[7-chloro-1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-2-methylindol-5-yl]oxyacetic acid	1192347: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRbeta expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	<0.0001	uM
5-[2,6-dichloro-4-(3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-N-(6,6-dimethyl-2-bicyclo[3.1.1]heptanyl)-2-hydroxybenzamide	213186: Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor	ki	<0.0001	uM
2-[3,5-dichloro-4-(4-hydroxy-3-piperidin-1-ylsulfonylphenoxy)phenyl]-1,2,4-triazine-3,5-dione	213186: Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor	ki	<0.0001	uM
2-[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-dimethylphenyl]-1,2,4-triazine-3,5-dione	213186: Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor	ki	<0.0001	uM
2-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]acetic acid	1797784: TRbeta-Binding Assay from Article 10.1021/jm021080f: “Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.”	ic50	<0.0001	uM
3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propanoic acid	1797784: TRbeta-Binding Assay from Article 10.1021/jm021080f: “Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.”	ic50	<0.0001	uM
5-[[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-dimethylphenyl]methyl]-1,3-thiazolidine-2,4-dione	307878: Agonist activity at THR in HepG2 cells by whole cell assay	ec50	0.0001	uM
N-cyclohexyl-5-[2,6-dichloro-4-(3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-2-hydroxybenzamide	213186: Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor	ki	0.0001	uM
3-[3,5-dichloro-4-(4-hydroxy-3-propan-2-ylphenoxy)phenyl]propanoic acid	1797785: TRbeta-Binding Assay and Thyroid Response Element (TRAFbeta1) Reporter Assay. from Article 10.1021/jm021080f: “Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.”	ic50	0.0001	uM
2-[7-chloro-1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]indol-5-yl]oxyacetic acid	1192347: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRbeta expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0001	uM
2-[1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-2,7-dimethylindol-5-yl]oxyacetic acid	1192347: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRbeta expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0001	uM
2-[7-chloro-1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-3-methylindol-5-yl]oxyacetic acid	1192347: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRbeta expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0001	uM
[2-[[(1S)-1-(3-chlorophenyl)-2-fluoroethyl]amino]-7-methoxy-1,3-benzoxazol-5-yl]-[(5R)-2-(2-hydroxyethyl)-2,5-dimethylmorpholin-4-yl]methanone	1678253: Inhibition of purified human plasma thrombin using Boc-Asp(OBzl)-Pro-Arg-AMC substrate incubated for 30 mins by fluorescence based assay	ic50	0.0001	uM
5-[2,6-dichloro-4-(3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-2-hydroxy-N-phenylbenzenesulfonamide	213186: Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor	ki	0.0001	uM
2-[3-chloro-4-(4-hydroxy-3-piperidin-1-ylsulfonylphenoxy)-5-methylphenyl]-1,2,4-triazine-3,5-dione	213186: Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor	ki	0.0001	uM
(2R)-2-amino-3-[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-diiodophenyl]propanoic acid	1797784: TRbeta-Binding Assay from Article 10.1021/jm021080f: “Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.”	ic50	0.0001	uM
6-[[3-(4-hydroxy-3-propan-2-ylphenoxy)-2,4-dimethylphenyl]methyl]-1,3-thiazinane-2,4-dione	307878: Agonist activity at THR in HepG2 cells by whole cell assay	ec50	0.0001	uM
Liothyronine	1799413: Competition Binding Assay from Article 10.1021/cb600311v: “Design and characterization of a thyroid hormone receptor alpha (TRalpha)-specific agonist.”	kd	0.0001	uM
2-amino-3-[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-diiodophenyl]propanoic acid	299948: Inhibition of human thyroid hormone receptor beta 1	ic50	0.0001	uM
2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propanoic acid	1417059: Agonist activity at GAL4 DNA-binding domain fused TRbeta receptor (unknown origin) ligand binding domain expressed in UAS-bla HEK 293T cells assessed as beta-lactamase transcriptional activation by FRET-based GeneBLAzer assay	ic50	0.0001	uM
2-[4-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-3,5-dimethylphenoxy]acetic acid	1799448: TR Receptor Ligand Binding Assay from Article 10.1016/s1074-5521(98)90168-5: “A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor.”	kd	0.0001	uM
2-[3,5-dibromo-4-(4-hydroxy-3-propan-2-ylphenoxy)phenyl]acetic acid	1797785: TRbeta-Binding Assay and Thyroid Response Element (TRAFbeta1) Reporter Assay. from Article 10.1021/jm021080f: “Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.”	ic50	0.0001	uM
4,6-dichloro-5-(4-hydroxy-3-propan-2-ylphenoxy)-1H-indole-2-carboxylic acid	261713: Inhibition of human TR-beta-1 by radioligand binding assay	ic50	0.0001	uM
3-[4-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-3,5-dimethylphenyl]propanoic acid	213184: Binding affinity of compound was determined against thyroid hormone receptor beta 1	kd	0.0002	uM
2-[1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-3,7-dimethylindol-5-yl]oxyacetic acid	1192347: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRbeta expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0002	uM
2-[3,5-dichloro-4-[3-(3-ethylphenyl)-4-hydroxyphenoxy]phenyl]acetic acid	1797796: TRbeta-Binding Assay from Article 10.1016/j.bmcl.2005.11.002: “Thyroid receptor ligands. Part 4: 4’-amido bioisosteric ligands selective for the thyroid hormone receptor beta.”	ic50	0.0002	uM
2-[4-[3-(2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-hydroxyphenoxy]-3,5-dichlorophenyl]-1,2,4-triazine-3,5-dione	213186: Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor	ki	0.0002	uM
2-[3,5-dichloro-4-(4-hydroxy-3-indol-1-ylsulfonylphenoxy)phenyl]-1,2,4-triazine-3,5-dione	213186: Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor	ki	0.0002	uM
(2S)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3-iodo-5-methylphenyl]propanoic acid	240275: Agonist activity towards thyroid hormone receptor expressed in human HepG2 cells	ec50	0.0002	uM
2-[3,5-dichloro-4-(4-hydroxy-3-propan-2-ylphenoxy)phenyl]acetic acid	345696: Displacement of [125I]3,5,3’-triiodo-L-thyronine His-tagged human recombinant TRbeta1 by scintillation proximity assay	ki	0.0002	uM
2-[4-(5-bromo-6-hydroxynaphthalen-1-yl)-3,5-dichloroanilino]-2-oxoacetic acid	254845: Inhibitory concentration against cloned human thyroid hormone receptor beta 1	ic50	0.0003	uM
3-[4-(5-bromo-6-hydroxynaphthalen-1-yl)-3,5-dichloroanilino]-3-oxopropanoic acid	254845: Inhibitory concentration against cloned human thyroid hormone receptor beta 1	ic50	0.0003	uM
4,6-dibromo-5-(4-hydroxy-3-propan-2-ylphenoxy)-1H-indole-2-carboxylic acid	261713: Inhibition of human TR-beta-1 by radioligand binding assay	ic50	0.0003	uM
2-[1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-7-methylindol-5-yl]oxyacetic acid	1192347: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRbeta expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0003	uM
2-[1-[(3-tert-butyl-4-hydroxyphenyl)methyl]-3-methylindol-5-yl]oxyacetic acid	1192347: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRbeta expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0003	uM
[2-[[(1S)-1-(3-chlorophenyl)-2-fluoroethyl]amino]-7-methoxy-1,3-benzoxazol-5-yl]-[5-(3-hydroxycyclobutyl)-2-methylmorpholin-4-yl]methanone	1678253: Inhibition of purified human plasma thrombin using Boc-Asp(OBzl)-Pro-Arg-AMC substrate incubated for 30 mins by fluorescence based assay	ic50	0.0003	uM
[2-[(3-chlorophenyl)methylamino]-7-methoxy-1,3-benzoxazol-5-yl]-[4-hydroxy-2-(2-hydroxyethyl)-5-methylpiperidin-1-yl]methanone	1678253: Inhibition of purified human plasma thrombin using Boc-Asp(OBzl)-Pro-Arg-AMC substrate incubated for 30 mins by fluorescence based assay	ic50	0.0003	uM
2-[6-(4-hydroxy-3-propan-2-ylphenoxy)-5,7-dimethyl-1-benzofuran-3-yl]acetic acid	307878: Agonist activity at THR in HepG2 cells by whole cell assay	ec50	0.0003	uM
(2S)-2-[[2-[3,5-dibromo-4-(4-hydroxy-3-propan-2-ylphenoxy)phenyl]acetyl]amino]-3-methylbutanoic acid	1797787: TRbeta-Binding Assay and Thyroid Response Element (TRAFbeta1) Reporter Assay. from Article 10.1016/j.bmcl.2007.05.049: “Thyroid receptor ligands. Part 8: Thyromimetics derived from N-acylated-alpha-amino acid derivatives displaying modulated pharmacological selectivity compared with KB-141.”	ic50	0.0003	uM
2-[3,5-dichloro-4-(4-hydroxy-3-spiro[8-azabicyclo[3.2.1]octane-3,2’-oxolane]-8-ylsulfonylphenoxy)phenyl]-1,2,4-triazine-3,5-dione	213186: Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor	ki	0.0003	uM
2-[3,5-dichloro-4-(4-hydroxy-3-spiro[1,3-dioxolane-2,3’-8-azabicyclo[3.2.1]octane]-8’-ylsulfonylphenoxy)phenyl]-1,2,4-triazine-3,5-dione	213186: Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor	ki	0.0003	uM
3-[3,5-dichloro-4-(6-methoxy-5-propan-2-ylnaphthalen-1-yl)anilino]-3-oxopropanoic acid	254845: Inhibitory concentration against cloned human thyroid hormone receptor beta 1	ic50	0.0003	uM
(2R)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propanoic acid	213175: Concentration required to inhibit 50% of I-T3 binding to hTR1 (Thyroid hormone receptor beta) was determined	ic50	0.0003	uM
2-[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-dimethylphenoxy]acetic acid	213185: Binding affinity of compound was determined against thyroid hormone receptor beta 1	kd	0.0004	uM
2-[4-[3-[(4-fluorophenyl)methyl]-4-hydroxyphenoxy]-3,5-dimethylphenyl]-1,2,4-triazine-3,5-dione	454513: Binding affinity to thyroid receptor beta	ki	0.0004	uM
3-[3,5-dibromo-4-(4-hydroxy-3-propan-2-ylphenoxy)anilino]-3-oxopropanoic acid	664440: Displacement of [125I]T3 from human recombinant thyroid harmone receptor beta after 16 to 48 hrs by gamma-ray detection	ki	0.0004	uM
2-[1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-3-methylindol-5-yl]oxyacetic acid	1192347: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRbeta expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0004	uM
[2-[[(1R)-1-(3-chlorophenyl)ethyl]amino]-7-methoxy-1,3-benzoxazol-5-yl]-[(2S,5R)-5-ethyl-2-(2-hydroxyethyl)-2-methylmorpholin-4-yl]methanone	1678253: Inhibition of purified human plasma thrombin using Boc-Asp(OBzl)-Pro-Arg-AMC substrate incubated for 30 mins by fluorescence based assay	ic50	0.0004	uM
N-cyclobutyl-5-[2,6-dichloro-4-(3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-2-hydroxybenzenesulfonamide	213186: Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor	ki	0.0004	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Triiodothyronine	affects binding, affects reaction, affects cotreatment, decreases activity, decreases reaction (+3 more)	31
bisphenol A	decreases reaction, increases methylation, increases reaction, increases expression, affects cotreatment (+4 more)	10
tetrabromobisphenol A	affects binding, decreases reaction, increases activity	8
Thyroxine	decreases reaction, decreases activity, increases reaction, increases activity, increases expression (+1 more)	8
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	8
Benzo(a)pyrene	decreases expression, decreases methylation, affects methylation	5
tetraiodothyroacetic acid	affects binding, increases activity, decreases reaction, increases reaction	4
tetrachlorodian	affects binding, decreases reaction, increases activity	4
3,3’,5-triiodothyroacetic acid	affects binding, increases activity, increases reaction	3
trichostatin A	affects cotreatment, increases expression	3
2,2’,4,4’-tetrabromodiphenyl ether	affects binding, affects reaction, decreases reaction, increases expression	3
bisphenol S	affects binding, decreases reaction, increases activity, increases reaction	3
Amiodarone	increases activity, increases expression, affects binding, decreases reaction	3
Diethylhexyl Phthalate	affects expression, affects binding, decreases activity, increases activity, decreases expression	3
Tretinoin	affects binding, decreases reaction, increases activity, increases expression	3
deoxynivalenol	decreases activity, decreases reaction, increases activity, affects cotreatment	2
2,5,2’,5’-tetrachlorobiphenyl	increases expression, decreases expression, increases abundance	2
methoxyacetic acid	increases activity, increases reaction	2
procymidone	affects binding, increases activity	2
acetochlor	affects binding, decreases activity	2
2,4,6-triiodophenol	affects binding, increases activity, decreases reaction	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
pyrachlostrobin	affects binding, increases activity	2
bisphenol AF	affects activity, affects binding, decreases reaction	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	increases abundance, increases oxidation, affects cotreatment, decreases expression	2
Doxorubicin	affects binding, decreases activity, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Carbaryl	affects binding, decreases activity	2

ChEMBL screening assays

169 unique, capped per target: 129 binding, 40 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1034533	Binding	Inhibition of SRC2 binding to human TRbeta receptor ligand binding domain expressed in Escherichia coli BL21 (DE3) by fluorescence polarization assay	Improvement of pharmacological properties of irreversible thyroid receptor coactivator binding inhibitors. — *J Med Chem*
CHEMBL1613771	Functional	PUBCHEM_BIOASSAY: Total Fluorescence Confirmation Counterscreen for Inhibitors of the Interaction of Thyroid Hormone Receptor and Steroid Receptor Coregulator 2, Fluorescein Fluoroprobe. (Class of assay: confirmatory) [Related pubchem assay	PubChem BioAssay data set

Cellosaurus cell lines

33 cell lines: 15 induced pluripotent stem cell, 11 cancer cell line, 3 embryonic stem cell, 3 transformed cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7M6	SEES3-1V human THRB, clone1	Embryonic stem cell	Male
CVCL_A7M7	SEES3-1V human THRB, clone2	Embryonic stem cell	Male
CVCL_A7M8	SEES3-1V human THRB, clone3	Embryonic stem cell	Male
CVCL_C0U8	HT22-BLRP-hTRb/pSV40-BirAV5	Transformed cell line
CVCL_C3GC	Hep-G2-THRB	Cancer cell line	Male
CVCL_C3GD	Hep-G2-THRB MUT p.K113N;T329P	Cancer cell line	Male
CVCL_C3GE	Hep-G2-THRB MUT p.K155E;K411E	Cancer cell line	Male
CVCL_C9SD	HPS1673	Induced pluripotent stem cell	Female
CVCL_C9SE	HPS1674	Induced pluripotent stem cell	Female
CVCL_C9SF	HPS1675	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00946296	Phase 4	COMPLETED	Impact of SSKI Pre-Treatment on Blood Loss in Thyroidectomy for Graves Disease
NCT03379181	Phase 4	COMPLETED	Thermogenesis in Hyperthyroidism and Effect of Anti-Adrenergic Therapy
NCT03393728	Phase 4	COMPLETED	Heart Rate Variability and Hyperthyroidism: Evaluation of the Short-term Effects of Propanolol
NCT05512715	Phase 4	COMPLETED	LIthium as Bridging thErapy Prior to Radioactiveiodine in hyperThYroidism
NCT01485211	Phase 4	COMPLETED	Corneal Thickness Changes During Corneal Collagen Cross-linking With Ultraviolet-A Irradiation and Riboflavin
NCT02119039	Phase 4	COMPLETED	Effect of CACICOL20 on Corneal Epithelial Healing After Cross-linking in Patients With Keratoconus
NCT03245853	Phase 4	COMPLETED	Epi-On Corneal Crosslinking for Keratoconus
NCT03429569	Phase 4	UNKNOWN	Cross-Linking ACcéléré Iontophorèse Confocal kératocONE
NCT04427956	Phase 4	COMPLETED	Corneal Crosslinking Treatment Study
NCT07474870	Phase 4	NOT_YET_RECRUITING	Outcomes of CTAK Surgery
NCT07629557	Phase 4	RECRUITING	Evaluate the Safety and Feasibility of Same-Day Bilateral Epithelium-On Corneal Cross-Linking for Keratoconus
NCT03303053	Phase 3	UNKNOWN	Efficacy and Safety of Cholestyramine and Prednisolone as Adjunctive Therapy in Treatment of Overt Hyperthyroidism
NCT04856488	Phase 3	RECRUITING	Preoperative Lugol’s Solution in Graves’ Disease and Toxic Nodular Goiter
NCT05118542	Phase 3	COMPLETED	Effect of Hyperthyroidism and Its Treatment in Graves’ Disease to Early Marker of Atherosclerosis
NCT00371202	Phase 3	UNKNOWN	Comparison of Penetrating Keratoplasty and Deep Lamellar Keratoplasty With the Big Bubble Technique for Keratoconus
NCT00647699	Phase 3	COMPLETED	Corneal Collagen Cross-linking for Progressive Keratoconus
NCT00815256	Phase 3	UNKNOWN	Safety and Effectiveness of Collagen Cross Linking in Progressive Mild and Moderate Keratoconus
NCT00887900	Phase 3	COMPLETED	Deep Anterior Lamellar Keratoplasty (DALK)
NCT01112072	Phase 3	UNKNOWN	Corneal Collagen Crosslinking and Intacs for Keratoconus and Ectasia
NCT01152541	Phase 3	UNKNOWN	Corneal Collagen Crosslinking for Progressive Keratoconus and Ectasia Using Riboflavin/Dextran and Hypotonic Riboflavin
NCT01190306	Phase 3	TERMINATED	Safety Study of the VEGA UV-A System to Treat Keratoconus
NCT01344187	Phase 3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01459679	Phase 3	TERMINATED	Safety & Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus or Corneal Ectasia After Refractive Surgery
NCT01464268	Phase 3	UNKNOWN	Transepithelial Corneal Collagen Crosslinking for Keratoconus and Corneal Ectasia
NCT01604135	Phase 3	ACTIVE_NOT_RECRUITING	Collagen Crosslinking for Keratoconus - a Randomized Controlled Clinical Trial
NCT01643226	Phase 3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01672814	Phase 3	COMPLETED	Microwave Treatment and Corneal Collagen Crosslinking for Keratoconus
NCT01682993	Phase 3	TERMINATED	Corneal Cross Linking and Topography Guided Excimer Laser Treatment
NCT01972854	Phase 3	TERMINATED	Safety and Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT02613780	Phase 3	UNKNOWN	Refractive Treatment of Early Keratoconus
NCT02638376	Phase 3	UNKNOWN	Evaluating the Safety and Efficacy of the KXL System for Corneal Collagen Cross-Linking in Eyes Having Keratoconus
NCT03080077	Phase 3	UNKNOWN	Safety and Effectiveness of Corneal Crosslinking (CXL): Keratoconus and Post-Refractive Ectasia
NCT03187912	Phase 3	COMPLETED	Accelerated Corneal Cross-linking With Different Riboflavin Solutions
NCT03442751	Phase 3	COMPLETED	Study to Evaluate the Safety and Efficacy of Epi-on Corneal Cross-linking in Eyes With Progressive Keratoconus
NCT03858036	Phase 3	UNKNOWN	Corneal Collagen Cross-Linking (CXL) Performed With Epi-ON Versus Epi-OFF in Eyes With Keratoconus and Other Corneal Ectatic Disorders
NCT04897503	Phase 3	UNKNOWN	Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Riboflavin/Dextran or Riboflavin/Methylcellulose
NCT04905108	Phase 3	UNKNOWN	Transepithelial (Epi-on) Corneal Collagen Crosslinking to Treat Keratoconus and Corneal Ectasia
NCT05027295	Phase 3	UNKNOWN	Accelerated Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Pulse or Continuous UV-A Light
NCT06100939	Phase 3	COMPLETED	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age With Keratoconus
NCT06100952	Phase 3	COMPLETED	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age With Keratoconus
NCT06450470	Phase 3	RECRUITING	Use of a Freeze-dried Amniotic Membrane Post Crosslinking in Subjects With Progressive Keratoconus
NCT06601101	Phase 3	RECRUITING	Effects of Topical Insulin on Corneal Epithelium Healing After Corneal Crosslinking in Patients With Keratoconus
NCT07124910	Phase 3	RECRUITING	Comparison of Epi-ON Corneal Collagen Crosslinking Performed Using an 18-Minute UVA Exposure vs. a 24-Minute UVA Exposure on Eyes With Ectatic Corneal Diseases
NCT07135167	Phase 3	RECRUITING	Compassionate Use Study of Epi-ON Corneal Collagen Crosslinking Performed Using UVA Exposure on Eyes With Ectatic Corneal Diseases for Subjects With Down Syndrome
NCT02203682	Phase 2	UNKNOWN	Doxycycline Treatment in Mild Thyroid-Associated Ophthalmopathy
NCT07369063	Phase 2	RECRUITING	Impact of Vitamin D Therapy on Thyroid Function and Antibody Levels in Pediatric Graves’ Disease
NCT00409955	Phase 2	COMPLETED	Lamellar Transplant With Lyophilized Corneas
NCT00925327	Phase 2	UNKNOWN	Safety and Effectiveness of the UV-X System for Corneal Collagen Cross-Linking for Compassionate Treatment in Pediatric Patients With Progressive Keratoconus
NCT01143389	Phase 2	COMPLETED	Corneal Crosslinking in Patients With Keratoconus and Post-Refractive Ectasia
NCT01181219	Phase 2	COMPLETED	Transepithelial Corneal Collagen Cross-linking (CXL) in Treatment of Keratoconus
NCT01325298	Phase 2	UNKNOWN	UVA-Riboflavin Crosslinking Treatment of Corneal Ectasia
NCT01809977	Phase 2	COMPLETED	Comparison of Partial Removal and Total Removal of the Corneal Epithelium on Keratoconus
NCT01843101	Phase 2	COMPLETED	Investigation of Different Scanning Protocols for 3 Dimensional High-resolution Imaging of the Human Cornea With Optical Coherence Tomography (OCT) - A Pilot Study
NCT01869517	Phase 2	UNKNOWN	Myoring Versus Keraring Implantation for Keratoconus
NCT01956474	Phase 2	TERMINATED	CXL-04 A Study of Collagen Crosslinking With Ultraviolet-A in Asymmetric Corneas
NCT02514200	Phase 2	UNKNOWN	Treatment of Keratoconus With Advanced CXL-II
NCT02762253	Phase 2	TERMINATED	Study of the Safety and Effectiveness of Photochemically Induced Collagen Cross-Linking in Eyes With Keratoconus.
NCT02827747	Phase 2	WITHDRAWN	The Role of Antioxidant Supplementation in Keratoconus Patients
NCT02834260	Phase 2	COMPLETED	Immunosuppression During Penetrating Keratoplasty, Using a Subconjunctival Implant Releasing Dexamethasone : Tolerance and Safety Pilot Study
NCT03029104	Phase 2	TERMINATED	Collagen Cross-Linking With Ultraviolet-A in Asymmetric Corneas

Predicted chemistry — Sugi Predict

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