Target Information

Target General Information

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Target ID

T61657 (Former ID: TTDR01191)

Target Name

Retinoic acid receptor beta (RARB)

Synonyms

RAR-epsilon; RAR-beta; Nuclear receptor subfamily 1 group B member 2; NR1B2; HBV-activated protein; HAP

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Gene Name

RARB

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Kaposi sarcoma [ICD-11: 2B57]

Function

Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence or presence of hormone ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function. Receptor for retinoic acid.

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BioChemical Class

Nuclear hormone receptor

UniProt ID

RARB_HUMAN

Sequence

MTTSGHACPVPAVNGHMTHYPATPYPLLFPPVIGGLSLPPLHGLHGHPPPSGCSTPSPAT
IETQSTSSEELVPSPPSPLPPPRVYKPCFVCQDKSSGYHYGVSACEGCKGFFRRSIQKNM
IYTCHRDKNCVINKVTRNRCQYCRLQKCFEVGMSKESVRNDRNKKKKETSKQECTESYEM
TAELDDLTEKIRKAHQETFPSLCQLGKYTTNSSADHRVRLDLGLWDKFSELATKCIIKIV
EFAKRLPGFTGLTIADQITLLKAACLDILILRICTRYTPEQDTMTFSDGLTLNRTQMHNA
GFGPLTDLVFTFANQLLPLEMDDTETGLLSAICLICGDRQDLEEPTKVDKLQEPLLEALK
IYIRKRRPSKPHMFPKILMKITDLRSISAKGAERVITLKMEIPGSMPPLIQEMLENSEGH
EPLTPSSSGNTAEHSPSISPSSVENSGVSQSPLVQ

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3D Structure

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PDB

HIT2.0 ID

T33VZN

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Alitretinoin

Drug Info

Approved

Kaposi sarcoma

[2], [3]

Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

Tamibarotene

Drug Info

Phase 3

T-cell leukaemia

[4]

Mode of Action

[+] 4 Modes of Action

Agonist

[+] 8 Agonist drugs

Alitretinoin

Drug Info

[1]

PMID27336223-Compound-10

Drug Info

[7]

PMID27336223-Compound-7

Drug Info

[7]

PMID27336223-Compound-8

Drug Info

[7]

AC261066

Drug Info

[8]

AC55649

Drug Info

[8]

BMS641

Drug Info

[10]

CD666

Drug Info

[11]

Modulator

[+] 1 Modulator drugs

Tamibarotene

Drug Info

[5], [6]

Antagonist

[+] 1 Antagonist drugs

AGN193109

Drug Info

[9]

Inhibitor

[+] 1 Inhibitor drugs

TTNPB

Drug Info

[12]

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: Tretinoin

Ligand Info

Structure Description

Crystal structure of RARb LBD in complex with 9cis retinoic acid

PDB:4DM8

Method

X-ray diffraction

Resolution

2.30 Å

Mutation

[13]

PDB Sequence

ESYEMTAELD

¹⁸⁷

DLTEKIRKAH

¹⁹⁷

QETFPSLCQL

²⁰⁷

GKYTTNSSAD

²¹⁷

HRVRLDLGLW

²²⁷

DKFSELATKC

²³⁷

IIKIVEFAKR

²⁴⁷

LPGFTGLTIA

²⁵⁷

DQITLLKAAC

²⁶⁷

LDILILRICT

²⁷⁷

RYTPEQDTMT

²⁸⁷

FSDGLTLNRT

²⁹⁷

QMHNAGFGPL

³⁰⁷

TDLVFTFANQ

³¹⁷

LLPLEMDDTE

³²⁷

TGLLSAICLI

³³⁷

CGDRQDLEEP

³⁴⁷

TKVDKLQEPL

³⁵⁷

LEALKIYIRK

³⁶⁷

RRPPHMFPKI

³⁷⁹

LMKITDLRSI

³⁸⁹

SAKGAERVIT

³⁹⁹

LKMEIPGSMP

⁴⁰⁹

PLIQEMLE

Residue

Distance (Å)

PHE201

3.435

TRP227

4.222

PHE230

3.693

LEU233

3.327

ALA234

3.546

CYS237

3.927

LYS240

4.954

LEU268

3.826

LEU271

3.529

ILE272

3.612

ILE275

4.059

ARG278

2.823

THR287

4.356

Residue

Distance (Å)

PHE288

3.611

SER289

2.626

GLY303

3.849

PHE304

4.097

LEU307

3.745

GLY393

4.151

ARG396

4.106

VAL397

4.389

LEU400

3.517

MET408

4.844

ILE412

3.823

LEU416

4.161

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

Ligand Name: BMS641

Ligand Info

Structure Description

Crystal structure of RARbeta LBD in complex with selective partial agonist BMS641 [3-chloro-4-[(E)-2-(5,5-dimethyl-8-phenyl-5,6-dihydronaphthalen-2-yl)ethenyl]benzoic acid]

PDB:4JYI

Method

X-ray diffraction

Resolution

1.90 Å

Mutation

[14]

PDB Sequence

SYEMTAELDD

¹⁷⁹

LTEKIRKAHQ

¹⁸⁹

ETFPSLCQLG

¹⁹⁹

KYTTNSSADH

²⁰⁹

RVRLDLGLWD

²¹⁹

KFSELATKCI

²²⁹

IKIVEFAKRL

²³⁹

PGFTGLTIAD

²⁴⁹

QITLLKAACL

²⁵⁹

DILILRICTR

²⁶⁹

YTPEQDTMTF

²⁷⁹

SDGLTLNRTQ

²⁸⁹

MHNAGFGPLT

²⁹⁹

DLVFTFANQL

³⁰⁹

LPLEMDDTET

³¹⁹

GLLSAICLIC

³²⁹

GDRQDLEEPT

³³⁹

KVDKLQEPLL

³⁴⁹

EALKIYIRKR

³⁵⁹

RPSKPHMFPK

³⁶⁹

ILMKITDLRS

³⁷⁹

ISAKGAERVI

³⁸⁹

TLKMEIPGSM

³⁹⁹

PPLIQEMME

Residue

Distance (Å)

PHE192

3.107

TRP218

3.932

PHE221

3.262

LEU224

3.789

ALA225

3.338

CYS228

3.656

LEU259

3.745

LEU262

3.498

ILE263

3.749

ARG265

4.479

ILE266

3.736

ARG269

3.395

PHE279

3.300

Residue

Distance (Å)

SER280

2.552

ASP281

4.883

GLY294

4.307

PHE295

3.372

LEU298

4.197

VAL302

4.081

GLY384

3.400

ARG387

4.034

VAL388

4.247

LEU391

4.229

MET399

4.846

ILE403

3.627

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). 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 Biological Network Descriptors

Different Human System Profiles of Target

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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).

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

Biological Network Descriptors

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

Degree	5	Degree centrality	5.37E-04	Betweenness centrality	1.27E-06
Closeness centrality	2.03E-01	Radiality	1.35E+01	Clustering coefficient	3.00E-01
Neighborhood connectivity	2.40E+01	Topological coefficient	3.47E-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-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Pathways in cancer

Small cell lung cancer

Non-small cell lung cancer

Reactome

[+] 1 Reactome Pathways

Nuclear Receptor transcription pathway

WikiPathways

[+] 5 WikiPathways

Vitamin A and Carotenoid Metabolism

Nuclear Receptors in Lipid Metabolism and Toxicity

Mesodermal Commitment Pathway

Integrated Pancreatic Cancer Pathway

Nuclear Receptors

References

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REF 1

Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):30-4.

REF 2

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: 2645).

REF 3

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 4

ClinicalTrials.gov (NCT04797780) SY-1425 Plus Azacitidine in Participants With Newly Diagnosed RARA-positive Higher-Risk Myelodysplastic Syndrome. U.S. National Institutes of Health.

REF 5

Tamibarotene: a candidate retinoid drug for Alzheimer's disease. Biol Pharm Bull. 2012;35(8):1206-12.

REF 6

A retinoic acid receptor agonist tamibarotene suppresses iron accumulation in the liver.Obesity (Silver Spring).2013 Jan;21(1):E22-5.

REF 7

Therapeutic use of selective synthetic ligands for retinoic acid receptors: a patent review.Expert Opin Ther Pat. 2016 Aug;26(8):957-71.

REF 8

Discovery of a potent, orally available, and isoform-selective retinoic acid beta2 receptor agonist. J Med Chem. 2005 Dec 1;48(24):7517-9.

REF 9

Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des. 2000 Jan;6(1):25-58.

REF 10

Rational design of RAR-selective ligands revealed by RARbeta crystal stucture. EMBO Rep. 2004 Sep;5(9):877-82.

REF 11

Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor gamma. Biochem Biophys Res Commun. 1992 Jul 31;186(2):977-83.

REF 12

9-cis-retinoic acid analogues with bulky hydrophobic rings: new RXR-selective agonists. Bioorg Med Chem Lett. 2004 Dec 20;14(24):6117-22.

REF 13

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors. Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):E588-94.

REF 14

An Unexpected Mode Of Binding Defines BMS948 as A Full Retinoic Acid Receptor beta (RARbeta, NR1B2) Selective Agonist. PLoS One. 2015 May 1;10(5):e0123195.

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