Target Binding Site Detail

Target General Information

Target ID

T79591

Target Info

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

Target Type

Successful Target

Gene Name

THRA

Biochemical Class

Nuclear hormone receptor

UniProt ID

THA_HUMAN

Ligand General Information

Top

Ligand Name

Liothyronine

Ligand Info

Canonical SMILES

C1=CC(=C(C=C1OC2=C(C=C(C=C2I)CC(C(=O)O)N)I)I)O

InChI

1S/C15H12I3NO4/c16-9-6-8(1-2-13(9)20)23-14-10(17)3-7(4-11(14)18)5-12(19)15(21)22/h1-4,6,12,20H,5,19H2,(H,21,22)/t12-/m0/s1

InChIKey

AUYYCJSJGJYCDS-LBPRGKRZSA-N

PubChem Compound ID

5920

Drug Binding Sites of Target

Top

PDB ID: 2H79 Crystal Structure of human TR alpha bound T3 in orthorhombic space group

Method

X-ray diffraction

Resolution

1.87 Å

Mutation

Yes

[1]

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

PDB ID: 2H77 Crystal structure of human TR alpha bound T3 in monoclinic space group

Method

X-ray diffraction

Resolution

2.33 Å

Mutation

Yes

[1]

PDB Sequence

RSLQQRPEPT

¹⁶¹

PEEWDLIHIA

¹⁷¹

TEAHRSTNAQ

¹⁸¹

GSHWKQRRKF

¹⁹¹

LPDDIGQSPI

²⁰¹

VSMPDGDKVD

²¹¹

LEAFSEFTKI

²²¹

ITPAITRVVD

²³¹

FAKKLPMFSE

²⁴¹

LPCEDQIILL

²⁵¹

KGCCMEIMSL

²⁶¹

RAAVRYDPES

²⁷¹

DTLTLSGEMA

²⁸¹

VKREQLKNGG

²⁹¹

LGVVSDAIFE

³⁰¹

LGKSLSAFNL

³¹¹

DDTEVALLQA

³²¹

VLLMSTDRSG

³³¹

LLVDKIEKSQ

³⁴²

EAYLLAFEHY

³⁵²

VNHRKHNIPH

³⁶²

FWPKLLMKVT

³⁷²

DLRMIGAHAS

³⁸³

RFLHKVEPTE

³⁹⁵

LFPPLFLEVF

⁴⁰⁵

Residue

Distance (Å)

ALA180

4.954

PHE215

4.237

PHE218

3.118

THR219

4.820

ILE221

3.993

ILE222

3.592

ALA225

3.631

ARG228

2.754

MET256

3.759

MET259

3.387

SER260

4.085

ARG262

3.637

ALA263

3.371

Residue

Distance (Å)

ARG266

4.452

THR275

3.542

LEU276

3.558

SER277

3.421

GLY278

4.348

LEU287

4.062

GLY290

3.524

GLY291

4.121

LEU292

3.637

ILE299

3.857

HIS381

2.680

PHE401

3.011

PDB ID: 4LNW Crystal structure of TR-alpha bound to T3 in a second site

Method

X-ray diffraction

Resolution

1.90 Å

Mutation

[2]

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)

ASN179

4.746

PHE215

3.938

PHE218

3.057

THR219

4.950

ILE221

3.911

ILE222

3.733

ALA225

3.673

ARG228

3.159

MET256

3.839

MET259

3.437

SER260

4.209

ARG262

3.542

ALA263

3.850

ARG266

4.238

THR275

3.580

LEU276

3.392

SER277

2.971

GLY278

4.256

Residue

Distance (Å)

LEU287

4.144

GLY290

3.569

GLY291

4.203

LEU292

3.596

ILE299

3.639

VAL322

4.851

SER326

3.649

GLU339

3.407

GLN342

2.691

LEU346

4.100

LEU368

3.244

MET369

3.831

VAL371

3.656

THR372

3.738

ARG375

2.959

HIS381

2.833

MET388

3.906

PHE401

3.313

PDB ID: 4LNX Crystal structure of TR-alpha bound to T4 in a second site

Method

X-ray diffraction

Resolution

2.05 Å

Mutation

[2]

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

Click to Show 3D Structure of This Binding Site

set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .T3 or .T32 or .T33 or :3T3;style chemicals stick;color identity;select .A:179 or .A:215 or .A:218 or .A:219 or .A:221 or .A:222 or .A:225 or .A:228 or .A:256 or .A:259 or .A:260 or .A:262 or .A:263 or .A:266 or .A:275 or .A:276 or .A:277 or .A:278 or .A:287 or .A:290 or .A:291 or .A:292 or .A:299 or .A:381 or .A:388 or .A:401; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all

Residue

Distance (Å)

ASN179

4.985

PHE215

3.960

PHE218

3.060

THR219

4.896

ILE221

3.937

ILE222

3.686

ALA225

3.721

ARG228

2.998

MET256

3.847

MET259

3.471

SER260

4.094

ARG262

3.504

ALA263

3.779

Residue

Distance (Å)

ARG266

4.112

THR275

3.567

LEU276

3.347

SER277

2.982

GLY278

4.157

LEU287

4.134

GLY290

3.397

GLY291

4.139

LEU292

3.522

ILE299

3.633

HIS381

2.909

MET388

3.994

PHE401

3.268

PDB ID: 7QDT Crystal structure of a mutant (P393GX) Thyroid Receptor Alpha ligand binding domain designed to model dominant negative human mutations.

Method

X-ray diffraction

Resolution

3.00 Å

Mutation

[3]

PDB Sequence

QRPEPTPEEW

¹⁶⁵

DLIHIATEAH

¹⁷⁵

RSTNAQGSHW

¹⁸⁵

KQRRKFLPDD

¹⁹⁵

IGQSPIVSMP

²⁰⁵

DGDKVDLEAF

²¹⁵

SEFTKIITPA

²²⁵

ITRVVDFAKK

²³⁵

LPMFSELPCE

²⁴⁵

DQIILLKGCC

²⁵⁵

MEIMSLRAAV

²⁶⁵

RYDPESDTLT

²⁷⁵

LSGEMAVKRE

²⁸⁵

QLKNGGLGVV

²⁹⁵

SDAIFELGKS

³⁰⁵

LSAFNLDDTE

³¹⁵

VALLQAVLLM

³²⁵

STDRSGLLCV

³³⁵

DKIEKSQEAY

³⁴⁵

LLAFEHYVNH

³⁵⁵

RKHNIPHFWP

³⁶⁵

KLLMKVTDLR

³⁷⁵

MIGACHASRF

³⁸⁵

LHMKVE

Click to Show 3D Structure of This Binding Site

set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .T3 or .T32 or .T33 or :3T3;style chemicals stick;color identity;select .A:179 or .A:215 or .A:218 or .A:221 or .A:222 or .A:225 or .A:228 or .A:256 or .A:259 or .A:260 or .A:262 or .A:263 or .A:266 or .A:275 or .A:276 or .A:277 or .A:278 or .A:287 or .A:290 or .A:291 or .A:292 or .A:299 or .A:381 or .A:384 or .A:385; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all

Residue

Distance (Å)

ASN179

4.318

PHE215

4.144

PHE218

3.473

ILE221

3.905

ILE222

3.726

ALA225

3.864

ARG228

2.806

MET256

3.728

MET259

3.490

SER260

4.219

ARG262

3.416

ALA263

3.749

ARG266

4.013

Residue

Distance (Å)

THR275

3.543

LEU276

3.261

SER277

2.949

GLY278

4.596

LEU287

4.087

GLY290

3.273

GLY291

3.990

LEU292

3.592

ILE299

3.942

HIS381

2.598

ARG384

2.706

PHE385

4.771

References

Top

REF 1

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 2

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

REF 3

Structure-Guided Approach to Relieving Transcriptional Repression in Resistance to Thyroid Hormone Alpha. Mol Cell Biol. 2022 Feb 17;42(2):e0036321.

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