Binding Site Information of Target

Target General Information

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Target ID

T94085

Target Info

Target Name

Retinoic acid receptor alpha (RARA)

Synonyms

RAR-alpha; RAR alpha; Nuclear receptor subfamily 1 group B member 1; NR1B1

Target Type

Clinical trial Target

Gene Name

RARA

Biochemical Class

Nuclear hormone receptor

UniProt ID

RARA_HUMAN

Drug Binding Sites of Target

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Ligand Name: Tretinoin

Ligand Info

Structure Description

Crystal structure of a mixed agonist-bound RAR-alpha and antagonist-bound RXR-alpha heterodimer ligand binding domains

PDB:3A9E

Method

X-ray diffraction

Resolution

2.75 Å

Mutation

[1]

PDB Sequence

SYTLTPEVGE

¹⁸⁶

LIEKVRKAHQ

¹⁹⁶

ETFPALCQLG

²⁰⁶

KYTTNNSSEQ

²¹⁶

RVSLDIDLWD

²²⁶

KFSELSTKCI

²³⁶

IKTVEFAKQL

²⁴⁶

PGFTTLTIAD

²⁵⁶

QITLLKAACL

²⁶⁶

DILILRICTR

²⁷⁶

YTPEQDTMTF

²⁸⁶

SDGLTLNRTQ

²⁹⁶

MHNAGFGPLT

³⁰⁶

DLVFAFANQL

³¹⁶

LPLEMDDAET

³²⁶

GLLSAICLIC

³³⁶

GDRQDLEQPD

³⁴⁶

RVDMLQEPLL

³⁵⁶

EALKVYVRKR

³⁶⁶

RPSRPHMFPK

³⁷⁶

MLMKITDLRS

³⁸⁶

ISAKGAERVI

³⁹⁶

TLKMEIPGSM

⁴⁰⁶

PPLIQEMLE

Residue

Distance (Å)

PHE199

3.704

TRP225

4.135

PHE228

3.301

LEU231

3.805

SER232

3.977

CYS235

3.518

LEU266

4.048

LEU269

3.616

ILE270

3.984

ARG272

4.684

ILE273

3.745

ARG276

3.637

PHE286

3.294

Residue

Distance (Å)

SER287

2.645

ASP288

4.510

GLY301

4.002

PHE302

3.984

LEU305

4.248

GLY391

4.059

ARG394

4.181

VAL395

3.513

LEU398

3.525

MET406

4.775

ILE410

4.404

LEU414

4.308

Ligand Name: PMID27336223-Compound-5

Ligand Info

Structure Description

Crystal structure of RARalpha ligand binding domain in complex with an agonist ligand (Am580) and a coactivator fragment

PDB:3KMR

Method

X-ray diffraction

Resolution

1.80 Å

Mutation

[2]

PDB Sequence

PEVGELIEKV

¹⁹¹

RKAHQETFPA

²⁰¹

LCQLGKYTTN

²¹¹

NSSEQRVSLD

²²¹

IDLWDKFSEL

²³¹

STKCIIKTVE

²⁴¹

FAKQLPGFTT

²⁵¹

LTIADQITLL

²⁶¹

KAACLDILIL

²⁷¹

RICTRYTPEQ

²⁸¹

DTMTFSDGLT

²⁹¹

LNRTQMHNAG

³⁰¹

FGPLTDLVFA

³¹¹

FANQLLPLEM

³²¹

DDAETGLLSA

³³¹

ICLICGDRQD

³⁴¹

LEQPDRVDML

³⁵¹

QEPLLEALKV

³⁶¹

YVRKRRPSRP

³⁷¹

HMFPKMLMKI

³⁸¹

TDLRSISAKG

³⁹¹

AERVITLKME

⁴⁰¹

IPGSMPPLIQ

⁴¹¹

EMLE

Residue

Distance (Å)

PHE199

4.778

TRP225

3.894

PHE228

3.433

SER229

4.915

LEU231

3.645

SER232

3.186

CYS235

3.808

LEU266

3.872

LEU269

3.262

ILE270

3.780

ARG272

4.441

ILE273

3.623

ARG276

2.961

Residue

Distance (Å)

PHE286

3.416

SER287

2.796

GLY301

3.945

PHE302

3.331

LEU305

4.214

GLY391

3.657

ARG394

4.230

VAL395

3.818

LEU398

3.569

MET406

4.791

ILE410

4.529

LEU414

3.732

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: Cysteine Sulfenic Acid

Ligand Info

Structure Description

Crystal structure of RARalpha ligand binding domain in complex with the inverse agonist BMS493 and a corepressor fragment

PDB:3KMZ

Method

X-ray diffraction

Resolution

2.10 Å

Mutation

[2]

PDB Sequence

TPEVGELIEK

¹⁹⁰

VRKAHQETFP

²⁰⁰

ALCQLGKYTT

²¹⁰

NNSSEQRVSL

²²⁰

DIDLWDKFSE

²³⁰

LSTKCIIKTV

²⁴⁰

EFAKQLPGFT

²⁵⁰

TLTIADQITL

²⁶⁰

LKAACLDILI

²⁷⁰

LRICTRYTPE

²⁸⁰

QDTMTFSDGL

²⁹⁰

TLNRTQMHNA

³⁰⁰

GFGPLTDLVF

³¹⁰

AFANQLLPLE

³²⁰

MDDAETGLLS

³³⁰

AICLICGDRQ

³⁴⁰

DLEQPDRVDM

³⁵⁰

LQEPLLEALK

³⁶⁰

VYVRKRRPSR

³⁷⁰

PHMFPKMLMK

³⁸⁰

ITDLRSISAK

³⁹⁰

GAERVITLKM

⁴⁰⁰

Click to Show 3D Structure of This Binding Site

set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CSO or .CSO2 or .CSO3 or :3CSO;style chemicals stick;color identity;select .B:262; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all

Residue

Distance (Å)

LYS262

3.777

Residue

Distance (Å)

Ligand Name: 4-{(E)-2-[5,5-dimethyl-8-(phenylethynyl)-5,6-dihydronaphthalen-2-yl]ethenyl}benzoic acid

Ligand Info

Structure Description

Crystal structure of RARalpha ligand binding domain in complex with the inverse agonist BMS493 and a corepressor fragment

PDB:3KMZ

Method

X-ray diffraction

Resolution

2.10 Å

Mutation

[2]

PDB Sequence

TPEVGELIEK

¹⁹⁰

VRKAHQETFP

²⁰⁰

ALCQLGKYTT

²¹⁰

NNSSEQRVSL

²²⁰

DIDLWDKFSE

²³⁰

LSTKCIIKTV

²⁴⁰

EFAKQLPGFT

²⁵⁰

TLTIADQITL

²⁶⁰

LKAACLDILI

²⁷⁰

LRICTRYTPE

²⁸⁰

QDTMTFSDGL

²⁹⁰

TLNRTQMHNA

³⁰⁰

GFGPLTDLVF

³¹⁰

AFANQLLPLE

³²⁰

MDDAETGLLS

³³⁰

AICLICGDRQ

³⁴⁰

DLEQPDRVDM

³⁵⁰

LQEPLLEALK

³⁶⁰

VYVRKRRPSR

³⁷⁰

PHMFPKMLMK

³⁸⁰

ITDLRSISAK

³⁹⁰

GAERVITLKM

⁴⁰⁰

Click to Show 3D Structure of This Binding Site

set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .EQO or .EQO2 or .EQO3 or :3EQO;style chemicals stick;color identity;select .B:199 or .B:225 or .B:228 or .B:229 or .B:231 or .B:232 or .B:233 or .B:235 or .B:236 or .B:266 or .B:269 or .B:270 or .B:272 or .B:273 or .B:276 or .B:285 or .B:286 or .B:287 or .B:301 or .B:302 or .B:305 or .B:309 or .B:387 or .B:391 or .B:394 or .B:396 or .B:398; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all

Residue

Distance (Å)

PHE199

3.333

TRP225

3.733

PHE228

3.463

SER229

3.766

LEU231

3.715

SER232

3.406

THR233

3.680

CYS235

3.602

ILE236

3.571

LEU266

3.935

LEU269

3.422

ILE270

3.790

ARG272

4.494

ILE273

3.669

Residue

Distance (Å)

ARG276

3.258

THR285

4.908

PHE286

3.361

SER287

2.628

GLY301

4.273

PHE302

3.610

LEU305

3.994

VAL309

4.254

ILE387

4.498

GLY391

3.923

ARG394

4.011

ILE396

4.553

LEU398

4.929

Ligand Name: 4-{5-(3-Tert-Butylphenyl)-1-[4-(Methylsulfonyl)phenyl]-1h-Pyrazol-3-Yl}benzoic Acid

Ligand Info

Structure Description

Crystal structure of the RAR alpha ligand-binding domain in complex with an antagonist

PDB:5K13

Method

X-ray diffraction

Resolution

1.85 Å

Mutation

[3]

PDB Sequence

TPEVGELIEK

¹⁹⁰

VRKAHQETFP

²⁰⁰

ALCQLGKYTT

²¹⁰

NNSSEQRVSL

²²⁰

DIDLWDKFSE

²³⁰

LSTKCIIKTV

²⁴⁰

EFAKQLPGFT

²⁵⁰

TLTIADQITL

²⁶⁰

LKAACLDILI

²⁷⁰

LRICTRYTPE

²⁸⁰

QDTMTFSDGL

²⁹⁰

TLNRTQMHNA

³⁰⁰

GFGPLTDLVF

³¹⁰

AFANQLLPLE

³²⁰

MDDAETGLLS

³³⁰

AICLICGDRQ

³⁴⁰

DLEQPDRVDM

³⁵⁰

LQEPLLEALK

³⁶⁰

VYVRKRRPSR

³⁷⁰

PHMFPKMLMK

³⁸⁰

ITDLRSISAK

³⁹⁰

GAERVITLKM

⁴⁰⁰

EIPGSMPPLI

⁴¹⁰

QEMLE

Click to Show 3D Structure of This Binding Site

set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .6Q7 or .6Q72 or .6Q73 or :36Q7;style chemicals stick;color identity;select .A:225 or .A:228 or .A:229 or .A:231 or .A:232 or .A:235 or .A:266 or .A:269 or .A:270 or .A:272 or .A:273 or .A:276 or .A:285 or .A:286 or .A:287 or .A:301 or .A:302 or .A:305 or .A:391 or .A:394 or .A:395 or .A:398 or .A:406 or .A:407 or .A:408 or .A:409 or .A:410; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all

Residue

Distance (Å)

TRP225

3.170

PHE228

3.371

SER229

4.629

LEU231

3.904

SER232

2.944

CYS235

3.742

LEU266

3.583

LEU269

3.412

ILE270

3.594

ARG272

4.589

ILE273

3.840

ARG276

2.972

THR285

4.920

PHE286

3.446

Residue

Distance (Å)

SER287

2.867

GLY301

3.684

PHE302

3.738

LEU305

4.089

GLY391

3.716

ARG394

3.621

VAL395

3.543

LEU398

4.278

MET406

3.608

PRO407

3.267

PRO408

4.634

LEU409

4.148

ILE410

4.076

Ligand Name: 4-[(4,4-Dimethyl-1,2,3,4-tetrahydro-[1,2']binapthalenyl-7-carbonyl)-amino]-benzoic acid

Ligand Info

Structure Description

CRYSTAL STRUCTURE OF A HETERODIMERIC COMPLEX OF RAR AND RXR LIGAND-BINDING DOMAINS

PDB:1DKF

Method

X-ray diffraction

Resolution

2.50 Å

Mutation

Yes

[4]

PDB Sequence

PEVGELIEKV

¹⁹¹

RKAHQETFPA

²⁰¹

LCQLGKYTTS

²¹⁴

EQRVSLDIDL

²²⁴

WDKFSELSTK

²³⁴

CIIKTVEFAK

²⁴⁴

QLPGFTTLTI

²⁵⁴

ADQITLLKAA

²⁶⁴

CLDILILRIC

²⁷⁴

TRYTPEQDTM

²⁸⁴

TFSDGLTLNR

²⁹⁴

TQMHNAGFGP

³⁰⁴

LTDLVFAFAN

³¹⁴

QLLPLEMDDA

³²⁴

ETGLLSAICL

³³⁴

ICGDRQDLEQ

³⁴⁴

PDRVDMLQEP

³⁵⁴

LLEALKVYVR

³⁶⁴

KRRPSRPHMF

³⁷⁴

PKMLMKITDL

³⁸⁴

RSISAKGAER

³⁹⁴

VITLKMEIPG

⁴⁰⁴

SMPPLIQEML

⁴¹⁴

Click to Show 3D Structure of This Binding Site

set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .BMS or .BMS2 or .BMS3 or :3BMS;style chemicals stick;color identity;select .B:199 or .B:225 or .B:228 or .B:229 or .B:231 or .B:232 or .B:233 or .B:235 or .B:236 or .B:266 or .B:269 or .B:270 or .B:272 or .B:273 or .B:276 or .B:285 or .B:286 or .B:287 or .B:288 or .B:301 or .B:302 or .B:305 or .B:391 or .B:392 or .B:394 or .B:395 or .B:398 or .B:406; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all

Residue

Distance (Å)

PHE199

3.398

TRP225

3.870

PHE228

3.343

SER229

3.075

LEU231

3.587

SER232

3.102

THR233

3.335

CYS235

3.461

ILE236

3.376

LEU266

4.060

LEU269

3.115

ILE270

3.673

ARG272

4.722

ILE273

2.982

Residue

Distance (Å)

ARG276

3.139

THR285

4.848

PHE286

3.350

SER287

2.759

ASP288

4.716

GLY301

3.985

PHE302

3.464

LEU305

3.994

GLY391

3.163

ALA392

4.690

ARG394

4.420

VAL395

3.904

LEU398

3.924

MET406

3.425

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: (5s)-4-[(3e,7e)-4,8-Dimethyl-10-(2,6,6-Trimethylcyclohex-1-En-1-Yl)deca-3,7-Dien-1-Yl]-5-Hydroxyfuran-2(5h)-One

Ligand Info

Structure Description

Revealing a marine natural product as a novel agonist for retinoic acid receptors with a unique binding mode and antitumor activity

PDB:4DQM

Method

X-ray diffraction

Resolution

2.75 Å

Mutation

[5]

PDB Sequence

PEVGELIEKV

¹⁹¹

RKAHQETFPA

²⁰¹

LCQLGKYTTN

²¹¹

NSSEQRVSLD

²²¹

IDLWDKFSEL

²³¹

STKCIIKTVE

²⁴¹

FAKQLPGFTT

²⁵¹

LTIADQITLL

²⁶¹

KAACLDILIL

²⁷¹

RICTRYTPEQ

²⁸¹

DTMTFSDGLT

²⁹¹

LNRTQMHNAG

³⁰¹

FGPLTDLVFA

³¹¹

FANQLLPLEM

³²¹

DDAETGLLSA

³³¹

ICLICGDRQD

³⁴¹

LEQPDRVDML

³⁵¹

QEPLLEALKV

³⁶¹

YVRKRRPSRP

³⁷¹

HMFPKMLMKI

³⁸¹

TDLRSISAKG

³⁹¹

AERVITLKME

⁴⁰¹

IPGSMPPLIQ

⁴¹¹

EMLE

Click to Show 3D Structure of This Binding Site

set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .LUF or .LUF2 or .LUF3 or :3LUF;style chemicals stick;color identity;select .A:199 or .A:225 or .A:228 or .A:231 or .A:232 or .A:234 or .A:235 or .A:236 or .A:266 or .A:269 or .A:270 or .A:272 or .A:273 or .A:276 or .A:285 or .A:286 or .A:287 or .A:288 or .A:301 or .A:302 or .A:305 or .A:391 or .A:394 or .A:395 or .A:398 or .A:406 or .A:414; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all

Residue

Distance (Å)

PHE199

3.721

TRP225

4.244

PHE228

3.057

LEU231

3.238

SER232

3.647

LYS234

4.342

CYS235

0.723

ILE236

4.738

LEU266

3.688

LEU269

2.950

ILE270

4.580

ARG272

3.794

ILE273

2.993

ARG276

3.385

Residue

Distance (Å)

THR285

4.133

PHE286

2.157

SER287

1.682

ASP288

3.985

GLY301

3.428

PHE302

3.747

LEU305

4.317

GLY391

3.927

ARG394

4.895

VAL395

3.494

LEU398

4.798

MET406

4.041

LEU414

3.386

References

Top

REF 1

The "Phantom Effect" of the Rexinoid LG100754: structural and functional insights. PLoS One. 2010 Nov 30;5(11):e15119.

REF 2

A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor. Nat Struct Mol Biol. 2010 Jul;17(7):801-7.

REF 3

Identification of potent and selective retinoic acid receptor gamma (RARGamma) antagonists for the treatment of osteoarthritis pain using structure based drug design. Bioorg Med Chem Lett. 2016 Jul 15;26(14):3274-3277.

REF 4

Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. Mol Cell. 2000 Feb;5(2):289-98.

REF 5

Revealing a natural marine product as a novel agonist for retinoic acid receptors with a unique binding mode and inhibitory effects on cancer cells. Biochem J. 2012 Aug 15;446(1):79-87.

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