Target Information

Target General Information

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Target ID

T60606 (Former ID: TTDS00452)

Target Name

Thyrotropin receptor (TSHR)

Synonyms

Thyroid stimulating hormone receptor; TSHR; TSH-R; TSH receptor

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Gene Name

TSHR

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Hypo-thyroidism [ICD-11: 5A00]

Thyroid cancer [ICD-11: 2D10]

Function

Receptor for thyrothropin. Plays a central role in controlling thyroid cell metabolism. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Also acts as a receptor for thyrostimulin (gpa2+gpb5).

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BioChemical Class

GPCR rhodopsin

UniProt ID

TSHR_HUMAN

Sequence

MRPADLLQLVLLLDLPRDLGGMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLI
ETHLRTIPSHAFSNLPNISRIYVSIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPD
ALKELPLLKFLGIFNTGLKMFPDLTKVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETL
TLKLYNNGFTSVQGYAFNGTKLDAVYLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTA
LPSKGLEHLKELIARNTWTLKKLPLSLSFLHLTRADLSYPSHCCAFKNQKKIRGILESLM
CNESSMQSLRQRKSVNALNSPLHQEYEENLGDSIVGYKEKSKFQDTHNNAHYYVFFEEQE
DEIIGFGQELKNPQEETLQAFDSHYDYTICGDSEDMVCTPKSDEFNPCEDIMGYKFLRIV
VWFVSLLALLGNVFVLLILLTSHYKLNVPRFLMCNLAFADFCMGMYLLLIASVDLYTHSE
YYNHAIDWQTGPGCNTAGFFTVFASELSVYTLTVITLERWYAITFAMRLDRKIRLRHACA
IMVGGWVCCFLLALLPLVGISSYAKVSICLPMDTETPLALAYIVFVLTLNIVAFVIVCCC
YVKIYITVRNPQYNPGDKDTKIAKRMAVLIFTDFICMAPISFYALSAILNKPLITVSNSK
ILLVLFYPLNSCANPFLYAIFTKAFQRDVFILLSKFGICKRQAQAYRGQRVPPKNSTDIQ
VQKVTHDMRQGLHNMEDVYELIENSHLTPKKQGQISEEYMQTVL

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3D Structure

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AlphaFold

HIT2.0 ID

T15YX5

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Thyrotropin

Drug Info

Approved

Hypothyroidism

[2]

Thyrotropin Alfa

Drug Info

Approved

Thyroid cancer

[3]

Mode of Action

[+] 3 Modes of Action

Modulator

[+] 1 Modulator drugs

Thyrotropin

Drug Info

[4]

Binder

[+] 1 Binder drugs

Thyrotropin Alfa

Drug Info

[1], [5]

Agonist

[+] 1 Agonist drugs

Recombinant TSH superagonists

Drug Info

[6]

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: Cholesterol

Ligand Info

Structure Description

TSHR-Gs-M22 antibody-ML109 complex

PDB:7XW6

Method

Electron microscopy

Resolution

2.78 Å

Mutation

Yes

[7]

PDB Sequence

PCECHQEEDF

³⁷

RVTCKDIQRI

⁴⁷

PSLPPSTQTL

⁵⁷

KLIETHLRTI

⁶⁷

PSHAFSNLPN

⁷⁷

ISRIYVSIDV

⁸⁷

TLQQLESHSF

⁹⁷

YNLSKVTHIE

¹⁰⁷

IRNTRNLTYI

¹¹⁷

DPDALKELPL

¹²⁷

LKFLGIFNTG

¹³⁷

LKMFPDLTKV

¹⁴⁷

YSTDIFFILE

¹⁵⁷

ITDNPYMTSI

¹⁶⁷

PVNAFQGLCN

¹⁷⁷

ETLTLKLYNN

¹⁸⁷

GFTSVQGYAF

¹⁹⁷

NGTKLDAVYL

²⁰⁷

NKNKYLTVID

²¹⁷

KDAFGGVYSG

²²⁷

PSLLDVSQTS

²³⁷

VTALPSKGLE

²⁴⁷

HLKELIARNT

²⁵⁷

WTLKKLPLSL

²⁶⁷

SFLHLTRADL

²⁷⁷

SYPIHCCAFK

²⁸⁷

NQKEDMVCTP

⁴⁰⁰

KSDEFNPCED

⁴¹⁰

IMGYKFLRIV

⁴²⁰

VWFVSLLALL

⁴³⁰

GNVFVLLILL

⁴⁴⁰

TSHYKLNVPR

⁴⁵⁰

FLMCNLAFAD

⁴⁶⁰

FCMGMYLLLI

⁴⁷⁰

ASVDLYTHSE

⁴⁸⁰

YYNHAIDWQT

⁴⁹⁰

GPGCNTAGFF

⁵⁰⁰

TVFASELSVY

⁵¹⁰

TLTVITLERW

⁵²⁰

YAITFAMRLD

⁵³⁰

RKIRLRHACA

⁵⁴⁰

IMVGGWVCCF

⁵⁵⁰

LLALLPLVGI

⁵⁶⁰

SSYAKVSICL

⁵⁷⁰

PMDTETPLAL

⁵⁸⁰

AYIVFVLTLN

⁵⁹⁰

IVAFVIVCCC

⁶⁰⁰

YVKIYITVRN

⁶¹⁰

PDKDTKIAKR

⁶²⁵

MAVLIFTDFI

⁶³⁵

CMAPISFYAL

⁶⁴⁵

SAILNKPLIT

⁶⁵⁵

VSNSKILLVL

⁶⁶⁵

FYPLNSCANP

⁶⁷⁵

FLYAIFTKAF

⁶⁸⁵

QRDVFILLSK

⁶⁹⁵

Residue

Distance (Å)

TYR414

2.834

LYS415

2.561

PHE416

2.298

LEU417

4.637

ARG418

2.429

ILE419

2.389

VAL420

2.610

TRP422

2.266

PHE423

2.352

LEU426

2.313

LEU427

2.467

LEU429

3.110

LEU430

2.252

GLY431

2.497

ASN432

4.600

PHE434

2.338

LEU468

2.317

ALA471

4.910

SER472

2.189

VAL473

4.792

LEU475

2.301

TYR476

2.321

HIS478

4.809

THR490

4.437

GLY491

3.895

PRO492

2.252

ASN495

2.362

THR496

2.365

PHE499

2.478

PHE500

2.587

SER505

4.613

GLU506

2.307

LEU507

4.002

VAL509

2.310

TYR510

2.083

THR513

2.203

VAL514

2.200

LEU517

2.636

ILE541

2.518

GLY545

4.775

TRP546

4.628

CYS548

4.096

CYS549

3.150

PHE550

2.373

LEU552

2.850

LEU554

2.376

LEU557

2.324

VAL558

2.402

VAL586

3.520

LEU589

2.223

Residue

Distance (Å)

ASN590

3.352

ILE591

2.549

VAL592

2.903

ALA593

2.215

PHE594

2.303

VAL595

2.346

ILE596

2.800

CYS598

2.866

CYS599

2.429

VAL602

2.216

LYS603

2.752

TYR605

3.165

ILE606

3.081

ARG609

4.008

ASP619

3.836

THR620

2.832

ALA623

2.317

LYS624

2.414

ALA627

2.223

VAL628

2.362

PHE631

2.505

THR632

4.902

PHE634

2.400

ILE635

2.894

MET637

2.747

ALA638

2.174

PRO639

2.283

SER641

2.233

PHE642

2.181

TYR643

2.079

LEU645

2.309

SER646

2.391

LEU649

2.209

LYS651

2.383

LEU653

2.508

ILE654

2.766

THR655

4.933

ASN658

2.332

ILE661

2.199

LEU662

2.580

LEU665

2.562

PHE666

2.374

LEU669

3.770

PHE676

2.362

ILE680

2.610

PHE681

2.918

PHE685

2.950

GLN686

2.374

VAL689

2.393

PHE690

2.333

Ligand Name: N-[4-[[5-[(2S)-3-benzyl-5-hydroxy-4-oxo-1,2-dihydroquinazolin-2-yl]-2-methoxyphenyl]methoxy]phenyl]acetamide

Ligand Info

Structure Description

TSHR-Gs-M22 antibody-ML109 complex

PDB:7XW6

Method

Electron microscopy

Resolution

2.78 Å

Mutation

Yes

[7]

PDB Sequence

PCECHQEEDF

³⁷

RVTCKDIQRI

⁴⁷

PSLPPSTQTL

⁵⁷

KLIETHLRTI

⁶⁷

PSHAFSNLPN

⁷⁷

ISRIYVSIDV

⁸⁷

TLQQLESHSF

⁹⁷

YNLSKVTHIE

¹⁰⁷

IRNTRNLTYI

¹¹⁷

DPDALKELPL

¹²⁷

LKFLGIFNTG

¹³⁷

LKMFPDLTKV

¹⁴⁷

YSTDIFFILE

¹⁵⁷

ITDNPYMTSI

¹⁶⁷

PVNAFQGLCN

¹⁷⁷

ETLTLKLYNN

¹⁸⁷

GFTSVQGYAF

¹⁹⁷

NGTKLDAVYL

²⁰⁷

NKNKYLTVID

²¹⁷

KDAFGGVYSG

²²⁷

PSLLDVSQTS

²³⁷

VTALPSKGLE

²⁴⁷

HLKELIARNT

²⁵⁷

WTLKKLPLSL

²⁶⁷

SFLHLTRADL

²⁷⁷

SYPIHCCAFK

²⁸⁷

NQKEDMVCTP

⁴⁰⁰

KSDEFNPCED

⁴¹⁰

IMGYKFLRIV

⁴²⁰

VWFVSLLALL

⁴³⁰

GNVFVLLILL

⁴⁴⁰

TSHYKLNVPR

⁴⁵⁰

FLMCNLAFAD

⁴⁶⁰

FCMGMYLLLI

⁴⁷⁰

ASVDLYTHSE

⁴⁸⁰

YYNHAIDWQT

⁴⁹⁰

GPGCNTAGFF

⁵⁰⁰

TVFASELSVY

⁵¹⁰

TLTVITLERW

⁵²⁰

YAITFAMRLD

⁵³⁰

RKIRLRHACA

⁵⁴⁰

IMVGGWVCCF

⁵⁵⁰

LLALLPLVGI

⁵⁶⁰

SSYAKVSICL

⁵⁷⁰

PMDTETPLAL

⁵⁸⁰

AYIVFVLTLN

⁵⁹⁰

IVAFVIVCCC

⁶⁰⁰

YVKIYITVRN

⁶¹⁰

PDKDTKIAKR

⁶²⁵

MAVLIFTDFI

⁶³⁵

CMAPISFYAL

⁶⁴⁵

SAILNKPLIT

⁶⁵⁵

VSNSKILLVL

⁶⁶⁵

FYPLNSCANP

⁶⁷⁵

FLYAIFTKAF

⁶⁸⁵

QRDVFILLSK

⁶⁹⁵

Residue

Distance (Å)

GLU404

2.375

PHE405

3.263

THR501

3.700

VAL502

2.226

SER505

3.467

GLU506

3.265

ILE568

3.462

LEU570

2.104

PRO571

2.649

MET572

2.255

THR574

3.205

TYR582

4.559

ILE583

2.401

VAL586

2.107

LEU587

2.656

Residue

Distance (Å)

ILE640

2.394

TYR643

3.350

ALA644

2.172

LEU645

4.545

ALA647

2.397

ILE648

2.157

PRO652

2.930

ILE654

2.343

THR655

2.943

VAL656

2.599

SER659

2.422

LYS660

4.234

LEU662

2.189

LEU663

2.467

TYR667

2.817

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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Leucine-rich repeat-containing GPCR 5 (LGR5)	PF00560 ; PF13855 ; PF01462 More >>	24.090 (172/714)	8.05E-44
Leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6)	PF13855	23.776 (170/715)	2.97E-32
Leucine-rich repeat and transmembrane domain-containing protein 2 (LRTM2)	PF13855 ; PF01462	33.684 (32/95)	6.68E-08
Reticulon-4 receptor (RTN4R)	PF13855	24.479 (47/192)	2.58E-07
Volume-regulated anion channel subunit LRRC8E (LRRC8E)	PF13855 ; PF12534	24.583 (59/240)	3.23E-06
Platelet glycoprotein V (GP5)	PF13855	28.095 (59/210)	5.87E-06
Olfactory receptor 4Q2 (OR4Q2)	PF13853	20.275 (59/291)	2.92E-05
Leucine-rich repeat-containing protein 4B (LRRC4B)	PF07679 ; PF13855	24.848 (41/165)	3.53E-05
Reticulon-4 receptor-like 2 (RTN4RL2)	PF13855	24.555 (69/281)	3.96E-05
Olfactory receptor 4D10 (OR4D10)	PF13853	20.879 (57/273)	8.05E-05
Leucine-rich repeat neuronal protein 1 (LRRN1)	PF07679 ; PF13855	22.556 (60/266)	1.29E-04
Olfactory receptor 4D2 (OR4D2)	PF13853	24.399 (71/291)	2.75E-04
Leucine-rich repeat-containing protein 4 (LRRC4)	PF07679 ; PF13855	21.801 (46/211)	4.32E-04
Insulin-like growth factor-binding protein complex acid labile subunit (IGFALS)	PF13855 ; PF01462	23.853 (52/218)	1.00E-03
Olfactory receptor 4D9 (OR4D9)	PF13853	23.529 (36/153)	1.00E-03
Decorin (DCN)	PF13855 ; PF01462	25.397 (64/252)	2.00E-03
Putative olfactory receptor 14L1 (OR14L1P)	PF13853	23.832 (51/214)	2.00E-03
Putative olfactory receptor 1F12P (OR1F12P)	PF13853	23.077 (30/130)	2.00E-03
Olfactory receptor 4D5 (OR4D5)	PF13853	25.781 (33/128)	3.00E-03
Olfactory receptor 4C13 (OR4C13)	PF13853	27.703 (41/148)	4.00E-03
Olfactory receptor 1L6 (OR1L6)	PF13853	22.006 (68/309)	5.00E-03
Olfactory receptor 14A16 (OR14A16)	PF13853	25.893 (29/112)	5.00E-03
Click to Show/Hide the Information of Human Similarity Proteins


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
cAMP signaling pathway	hsa04024	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Thyroid hormone synthesis	hsa04918	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Regulation of lipolysis in adipocytes	hsa04923	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Degree	2	Degree centrality	2.15E-04	Betweenness centrality	2.02E-04
Closeness centrality	2.03E-01	Radiality	1.35E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	1.45E+01	Topological coefficient	5.00E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 4 KEGG Pathways

cAMP signaling pathway

Neuroactive ligand-receptor interaction

Thyroid hormone synthesis

Autoimmune thyroid disease

NetPath Pathway

[+] 1 NetPath Pathways

Wnt Signaling Pathway

PID Pathway

[+] 2 PID Pathways

Arf6 trafficking events

Arf6 signaling events

Reactome

[+] 2 Reactome Pathways

Hormone ligand-binding receptors

G alpha (s) signalling events

WikiPathways

[+] 5 WikiPathways

Peptide GPCRs

TSH signaling pathway

Thyroxine (Thyroid Hormone) Production

GPCR ligand binding

GPCR downstream signaling

References

Top

REF 1

Pharmacological profiles and clinical effects of recombinant human thyrotropin alfa (Thyrogen) Intramuscular Injection 0.9 mg). Nippon Yakurigaku Zasshi. 2009 Jul;134(1):28-34.

REF 2

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

REF 3

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 020898.

REF 4

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

REF 5

Diagnosis of poorly differentiated thyroid cancer with radioiodine scanning after thyrotropin alfa stimulation. N Engl J Med. 2008 Sep 18;359(12):1295-7.

REF 6

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. (Target id: 255).

REF 7

Hormone- and antibody-mediated activation of the thyrotropin receptor. Nature. 2022 Sep;609(7928):854-859.

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