Target Information

Target General Information

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Target ID

T82146 (Former ID: TTDS00075)

Target Name

Retinoic acid receptor gamma (RARG)

Synonyms

RAR-gamma; Nuclear receptor subfamily 1 group B member 3; NR1B3

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Gene Name

RARG

Target Type

Successful target

[1]

Disease

[+] 5 Target-related Diseases

Acne vulgaris [ICD-11: ED80]

Acute myeloid leukaemia [ICD-11: 2A60]

Kaposi sarcoma [ICD-11: 2B57]

Muscle calcification/ossification [ICD-11: FB31]

Psoriasis [ICD-11: EA90]

Function

Receptor for retinoic acid. 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 RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. Required for limb bud development. In concert with RARA or RARB, required for skeletal growth, matrix homeostasis and growth plate function (By similarity).

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BioChemical Class

Nuclear hormone receptor

UniProt ID

RARG_HUMAN

Sequence

MATNKERLFAAGALGPGSGYPGAGFPFAFPGALRGSPPFEMLSPSFRGLGQPDLPKEMAS
LSVETQSTSSEEMVPSSPSPPPPPRVYKPCFVCNDKSSGYHYGVSSCEGCKGFFRRSIQK
NMVYTCHRDKNCIINKVTRNRCQYCRLQKCFEVGMSKEAVRNDRNKKKKEVKEEGSPDSY
ELSPQLEELITKVSKAHQETFPSLCQLGKYTTNSSADHRVQLDLGLWDKFSELATKCIIK
IVEFAKRLPGFTGLSIADQITLLKAACLDILMLRICTRYTPEQDTMTFSDGLTLNRTQMH
NAGFGPLTDLVFAFAGQLLPLEMDDTETGLLSAICLICGDRMDLEEPEKVDKLQEPLLEA
LRLYARRRRPSQPYMFPRMLMKITDLRGISTKGAERAITLKMEIPGPMPPLIREMLENPE
MFEDDSSQPGPHPNASSEDEVPGGQGKGGLKSPA

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3D Structure

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PDB

HIT2.0 ID

T80D9C

Drugs and Modes of Action

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Approved Drug(s)

[+] 5 Approved Drugs

Alitretinoin

Drug Info

Approved

Kaposi sarcoma

[2], [3]

Palovarotene

Drug Info

Approved

Fibrodysplasia ossificans progressiva

[4]

Tazarotene

Drug Info

Approved

Psoriasis vulgaris

[3], [5]

Tretinoin

Drug Info

Approved

Acne vulgaris

[3], [6]

Trifarotene

Drug Info

Approved

Acne vulgaris

[7]

Mode of Action

[+] 5 Modes of Action

Modulator

[+] 1 Modulator drugs

Alitretinoin

Drug Info

[8], [9], [10]

Agonist

[+] 9 Agonist drugs

Palovarotene

Drug Info

[4]

Tretinoin

Drug Info

[9]

Trifarotene

Drug Info

[7]

PMID27336223-Compound-12

Drug Info

[11]

PMID27336223-Compound-13

Drug Info

[11]

PMID27336223-Compound-14

Drug Info

[11]

AHPN

Drug Info

[13]

BMS270394

Drug Info

[15]

CD666

Drug Info

[16]

Binder

[+] 1 Binder drugs

Tazarotene

Drug Info

[1]

Antagonist

[+] 2 Antagonist drugs

AGN193109

Drug Info

[12]

MM 11253

Drug Info

[18]

Inhibitor

[+] 4 Inhibitor drugs

BMS184394

Drug Info

[14]

CD564

Drug Info

[14]

Dodecyl-Alpha-D-Maltoside

Drug Info

[17]

SR11254

Drug Info

[14]

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

LIGAND-BINDING DOMAIN OF THE HUMAN RETINOIC ACID RECEPTOR GAMMA BOUND TO ALL-TRANS RETINOIC ACID

PDB:2LBD

Method

X-ray diffraction

Resolution

2.06 Å

Mutation

[19]

PDB Sequence

LSPQLEELIT

¹⁹¹

KVSKAHQETF

²⁰¹

PSLCQLGKYT

²¹¹

TNSSADHRVQ

²²¹

LDLGLWDKFS

²³¹

ELATKCIIKI

²⁴¹

VEFAKRLPGF

²⁵¹

TGLSIADQIT

²⁶¹

LLKAACLDIL

²⁷¹

MLRICTRYTP

²⁸¹

EQDTMTFSDG

²⁹¹

LTLNRTQMHN

³⁰¹

AGFGPLTDLV

³¹¹

FAFAGQLLPL

³²¹

EMDDTETGLL

³³¹

SAICLICGDR

³⁴¹

MDLEEPEKVD

³⁵¹

KLQEPLLEAL

³⁶¹

RLYARRRRPS

³⁷¹

QPYMFPRMLM

³⁸¹

KITDLRGIST

³⁹¹

KGAERAITLK

⁴⁰¹

MEIPGPMPPL

⁴¹¹

IREMLENP

Residue

Distance (Å)

PHE201

3.327

TRP227

4.401

PHE230

3.381

LEU233

4.016

ALA234

4.364

CYS237

3.841

LEU268

4.051

LEU271

3.575

MET272

3.694

ARG274

3.700

ILE275

3.162

ARG278

2.219

THR287

4.946

PHE288

3.325

Residue

Distance (Å)

SER289

1.762

ASP290

4.250

GLY303

4.021

PHE304

3.861

LEU307

4.395

GLY393

3.580

ARG396

4.127

ALA397

4.041

LEU400

3.440

MET408

4.326

ILE412

4.142

MET415

4.099

LEU416

4.733

Ligand Name: Alitretinoin

Ligand Info

Structure Description

RARg mutant-S371E

PDB:5M24

Method

X-ray diffraction

Resolution

1.69 Å

Mutation

Yes

[20]

PDB Sequence

LSPQLEELIT

¹⁹¹

KVSKAHQETF

²⁰¹

PSLCQLGKYT

²¹¹

TNSSADHRVQ

²²¹

LDLGLWDKFS

²³¹

ELATKCIIKI

²⁴¹

VEFAKRLPGF

²⁵¹

TGLSIADQIT

²⁶¹

LLKAACLDIL

²⁷¹

MLRICTRYTP

²⁸¹

EQDTMTFSDG

²⁹¹

LTLNRTQMHN

³⁰¹

AGFGPLTDLV

³¹¹

FAFAGQLLPL

³²¹

EMDDTETGLL

³³¹

SAICLICGDR

³⁴¹

MDLEEPEKVD

³⁵¹

KLQEPLLEAL

³⁶¹

RLYARRRRPE

³⁷¹

QPYMFPRMLM

³⁸¹

KITDLRGIST

³⁹¹

KGAERAITLK

⁴⁰¹

MEIPGPMPPL

⁴¹¹

IREMLE

Residue

Distance (Å)

PHE201

4.880

TRP227

3.942

PHE230

3.399

LEU233

3.811

ALA234

3.585

CYS237

4.131

LEU268

3.795

LEU271

3.565

MET272

3.665

ARG274

4.957

ILE275

3.771

ARG278

2.797

THR287

4.728

Residue

Distance (Å)

PHE288

3.475

SER289

2.692

GLY303

4.431

PHE304

3.777

LEU307

4.406

GLY393

3.529

ARG396

4.870

ALA397

4.213

LEU400

3.596

MET408

4.373

ILE412

3.800

MET415

4.016

LEU416

4.526

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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	1.15E-06
Closeness centrality	2.02E-01	Radiality	1.35E+01	Clustering coefficient	5.00E-01
Neighborhood connectivity	2.16E+01	Topological coefficient	3.38E-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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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

Endoderm Differentiation

Nuclear Receptors

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Recent developments in receptor-selective retinoids. Curr Pharm Des. 2000 Jun;6(9):919-31.

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

FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 215559

REF 5

REF 6

REF 7

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019

REF 8

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 9

Targacept active conformation search: a new method for predicting the conformation of a ligand bound to its protein target. J Med Chem. 2004 Dec 30;47(27):6831-9.

REF 10

Alitretinoin: a comprehensive review. Expert Opin Investig Drugs. 2008 Mar;17(3):437-43.

REF 11

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

REF 12

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

REF 13

Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes. J Med Chem. 1995 Dec 22;38(26):4993-5006.

REF 14

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 15

Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARgamma. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6322-7.

REF 16

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 17

DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.

REF 18

Modulation of retinoic acid receptor function alters the growth inhibitory response of oral SCC cells to retinoids. Oncogene. 2000 Mar 9;19(11):1457-65.

REF 19

Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature. 1995 Dec 14;378(6558):681-9.

REF 20

Allosteric Regulation in the Ligand Binding Domain of Retinoic Acid ReceptorGamma. PLoS One. 2017 Jan 26;12(1):e0171043.

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