Target Information

Target General Information

Target ID

T79591 (Former ID: TTDS00381)

Target Name

Thyroid hormone receptor alpha (THRA)

Synonyms

V-erbA-related protein 7; THRA2; THRA1; Nuclear receptor subfamily 1 group A member 1; NR1A1; ERBA1; EAR7; EAR-7; C-erbA-alpha; C-erbA-1

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Gene Name

THRA

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Hyper-lipoproteinaemia [ICD-11: 5C80]

Hypo-thyroidism [ICD-11: 5A00]

Function

High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. Isoform Alpha-1: Nuclear hormone receptor that can act as a repressor or activator of transcription.

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BioChemical Class

Nuclear hormone receptor

UniProt ID

THA_HUMAN

Sequence

MEQKPSKVECGSDPEENSARSPDGKRKRKNGQCSLKTSMSGYIPSYLDKDEQCVVCGDKA
TGYHYRCITCEGCKGFFRRTIQKNLHPTYSCKYDSCCVIDKITRNQCQLCRFKKCIAVGM
AMDLVLDDSKRVAKRKLIEQNRERRRKEEMIRSLQQRPEPTPEEWDLIHIATEAHRSTNA
QGSHWKQRRKFLPDDIGQSPIVSMPDGDKVDLEAFSEFTKIITPAITRVVDFAKKLPMFS
ELPCEDQIILLKGCCMEIMSLRAAVRYDPESDTLTLSGEMAVKREQLKNGGLGVVSDAIF
ELGKSLSAFNLDDTEVALLQAVLLMSTDRSGLLCVDKIEKSQEAYLLAFEHYVNHRKHNI
PHFWPKLLMKEREVQSSILYKGAAAEGRPGGSLGVHPEGQQLLGMHVVQGPQVRQLEQQL
GEAGSLQGPVLQHQSPKSPQQRLLELLHRSGILHARAVCGEDDSSEADSPSSSEEEPEVC
EDLAGNAASP

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Approved Drug(s)

[+] 3 Approved Drugs

Dextrothyroxine Sodium

Drug Info

Approved

High blood cholesterol level

[2]

Levothyroxine

Drug Info

Approved

Hypothyroidism

[3], [4]

Liothyronine

Drug Info

Approved

Hypothyroidism

[2]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

BCT303

Drug Info

Phase 2

Hypothyroidism

[5]

tiratricol

Drug Info

Clinical trial

Wound healing

[6]

Mode of Action

[+] 4 Modes of Action

Modulator

[+] 2 Modulator drugs

Dextrothyroxine Sodium

Drug Info

[7]

BCT303

Drug Info

[10]

Antagonist

[+] 2 Antagonist drugs

Levothyroxine

Drug Info

[8], [9]

Liothyronine

Drug Info

[1], [9]

Agonist

[+] 2 Agonist drugs

tiratricol

Drug Info

[11]

rT3

Drug Info

[11]

Inhibitor

[+] 12 Inhibitor drugs

(3,5-Dibromo-4-hexyloxy-phenyl)-acetic acid

Drug Info

[12]

(E)-1-(4-heptylphenyl)but-2-en-1-one

Drug Info

[13]

(Z)-4-(4-hexylphenylamino)-4-oxobut-2-enoic acid

Drug Info

[13]

1-(4-hexylphenyl)-3-morpholinopropan-1-one

Drug Info

[13]

3-(3,5-Dibromo-4-hexyloxy-phenyl)-propionic acid

Drug Info

[12]

3-(4-(benzyloxy)-3,5-dibromophenyl)propanoic acid

Drug Info

[14]

3-(dibutylamino)-1-(4-hexylphenyl)propan-1-one

Drug Info

[13]

3-(dimethylamino)-1-(4-hexylphenyl)propan-1-one

Drug Info

[13]

3-bromo-1-(4-hexylphenyl)propan-1-one

Drug Info

[13]

4-(4-hexylphenyl)-4-oxobut-2-enoic acid

Drug Info

[13]

4-hexylphenyl propiolate

Drug Info

[13]

Detrothyronine

Drug Info

[15]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Liothyronine

Ligand Info

Structure Description

Crystal Structure of human TR alpha bound T3 in orthorhombic space group

PDB:2H79

Method

X-ray diffraction

Resolution

1.87 Å

Mutation

Yes

[16]

PDB Sequence

ARGSHMEEMI

¹⁵¹

RSLQQRPEPT

¹⁶¹

PEEWDLIHIA

¹⁷¹

TEAHRSTNAQ

¹⁸¹

GSHWKQRRKF

¹⁹¹

LPDDIGQSPI

²⁰¹

VSMPDGDKVD

²¹¹

LEAFSEFTKI

²²¹

ITPAITRVVD

²³¹

FAKKLPMFSE

²⁴¹

LPEDQIILLK

²⁵²

GCCMEIMSLR

²⁶²

AAVRYDPESD

²⁷²

TLTLSGEMAV

²⁸²

KREQLKNGGL

²⁹²

GVVSDAIFEL

³⁰²

GKSLSAFNLD

³¹²

DTEVALLQAV

³²²

LLMSTDRSGL

³³²

LVDKIEKSQE

³⁴³

AYLLAFEHYV

³⁵³

NHRKHNIPHF

³⁶³

WPKLLMKVTD

³⁷³

LRMIGAHASR

³⁸⁴

FLHKVEPTEL

³⁹⁶

FPPLFLEVFE

⁴⁰⁶

Residue

Distance (Å)

ASN179

4.833

PHE215

4.001

PHE218

3.054

THR219

4.886

ILE221

3.953

ILE222

3.570

ALA225

3.625

ARG228

3.051

MET256

3.735

MET259

3.457

SER260

4.224

ARG262

3.501

ALA263

3.720

Residue

Distance (Å)

ARG266

4.120

THR275

3.562

LEU276

3.410

SER277

2.994

GLY278

4.212

LEU287

4.266

GLY290

3.483

GLY291

4.214

LEU292

3.559

ILE299

3.546

HIS381

2.772

PHE401

3.321

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Ligand Name: Levothyroxine

Ligand Info

Structure Description

Crystal structure of TR-alpha bound to T4 in a second site

PDB:4LNX

Method

X-ray diffraction

Resolution

2.05 Å

Mutation

[17]

PDB Sequence

SHMEEMIRSL

¹⁵⁴

QQRPEPTPEE

¹⁶⁴

WDLIHIATEA

¹⁷⁴

HRSTNAQGSH

¹⁸⁴

WKQRRKFLPD

¹⁹⁴

DIGQSPIVSM

²⁰⁴

PDGDKVDLEA

²¹⁴

FSEFTKIITP

²²⁴

AITRVVDFAK

²³⁴

KLPMFSELPE

²⁴⁵

DQIILLKGCC

²⁵⁵

MEIMSLRAAV

²⁶⁵

RYDPESDTLT

²⁷⁵

LSGEMAVKRE

²⁸⁵

QLKNGGLGVV

²⁹⁵

SDAIFELGKS

³⁰⁵

LSAFNLDDTE

³¹⁵

VALLQAVLLM

³²⁵

STDRSGLLVD

³³⁶

KIEKSQEAYL

³⁴⁶

LAFEHYVNHR

³⁵⁶

KHNIPHFWPK

³⁶⁶

LLMKVTDLRM

³⁷⁶

IGAHASRFLH

³⁸⁷

MKVEPTELFP

³⁹⁸

PLFLEVFED

Residue

Distance (Å)

VAL322

4.984

SER326

3.612

GLU339

3.301

GLN342

2.878

LEU346

4.427

Residue

Distance (Å)

LEU368

3.233

VAL371

3.877

THR372

3.629

ARG375

2.755

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Thyroid hormone signaling pathway	hsa04919	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Degree	6	Degree centrality	6.45E-04	Betweenness centrality	1.96E-05
Closeness centrality	2.22E-01	Radiality	1.39E+01	Clustering coefficient	4.67E-01
Neighborhood connectivity	4.70E+01	Topological coefficient	2.41E-01	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Neuroactive ligand-receptor interaction

Thyroid hormone signaling pathway

PID Pathway

[+] 1 PID Pathways

RXR and RAR heterodimerization with other nuclear receptor

Reactome

[+] 1 Reactome Pathways

Nuclear Receptor transcription pathway

WikiPathways

[+] 2 WikiPathways

Endochondral Ossification

Nuclear Receptors

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

Evaluation of thyroid hormone action in a case of generalized resistance to thyroid hormone with chronic thyroiditis: discovery of a novel heterozy... Endocr J. 2007 Dec;54(5):727-32.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 3

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4627).

REF 4

Current methodology to assess bioequivalence of levothyroxine sodium products is inadequate. AAPS J. 2005 Mar 30;7(1):E42-6.

REF 5

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800037654)

REF 6

REF 7

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 8

Thyroid hormone resistance and pituitary enlargement after thyroid ablation in a woman on levothyroxine treatment. Thyroid. 2008 Oct;18(10):1119-23.

REF 9

Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab. 2007 Mar;3(3):249-59.

REF 10

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 11

Binding of 3,5,3'-triiodothyronine (T3) and its analogs to the in vitro translational products of c-erbA protooncogenes: differences in the affinity of the alpha- and beta-forms for the acetic acid analog and failure of the human testis and kidney alpha-2 products to bind T3. Mol Endocrinol. 1990 Feb;4(2):227-34.

REF 12

Thyroid receptor ligands. 3. Design and synthesis of 3,5-dihalo-4-alkoxyphenylalkanoic acids as indirect antagonists of the thyroid hormone receptor. J Med Chem. 2005 May 5;48(9):3114-7.

REF 13

Inhibitors of the interaction of a thyroid hormone receptor and coactivators: preliminary structure-activity relationships. J Med Chem. 2007 Nov 1;50(22):5269-80.

REF 14

Thyroid receptor ligands. Part 7: Indirect antagonists of the thyroid hormone receptor with improved affinity. Bioorg Med Chem Lett. 2007 Apr 1;17(7):2018-21.

REF 15

Thyroid receptor ligands. Part 5: novel bicyclic agonist ligands selective for the thyroid hormone receptor beta. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1240-4.

REF 16

Structural rearrangements in the thyroid hormone receptor hinge domain and their putative role in the receptor function. J Mol Biol. 2006 Jul 14;360(3):586-98.

REF 17

Identification of a new hormone-binding site on the surface of thyroid hormone receptor. Mol Endocrinol. 2014 Apr;28(4):534-45.

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