Target Information
Target General Information | Top | |||||
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Target ID |
T82146
(Former ID: TTDS00075)
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Target Name |
Retinoic acid receptor gamma (RARG)
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Synonyms |
RAR-gamma; Nuclear receptor subfamily 1 group B member 3; NR1B3
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Gene Name |
RARG
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 5 Target-related Diseases | + | ||||
1 | Acne vulgaris [ICD-11: ED80] | |||||
2 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
3 | Kaposi sarcoma [ICD-11: 2B57] | |||||
4 | Muscle calcification/ossification [ICD-11: FB31] | |||||
5 | 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
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UniProt ID | ||||||
Sequence |
MATNKERLFAAGALGPGSGYPGAGFPFAFPGALRGSPPFEMLSPSFRGLGQPDLPKEMAS
LSVETQSTSSEEMVPSSPSPPPPPRVYKPCFVCNDKSSGYHYGVSSCEGCKGFFRRSIQK NMVYTCHRDKNCIINKVTRNRCQYCRLQKCFEVGMSKEAVRNDRNKKKKEVKEEGSPDSY ELSPQLEELITKVSKAHQETFPSLCQLGKYTTNSSADHRVQLDLGLWDKFSELATKCIIK IVEFAKRLPGFTGLSIADQITLLKAACLDILMLRICTRYTPEQDTMTFSDGLTLNRTQMH NAGFGPLTDLVFAFAGQLLPLEMDDTETGLLSAICLICGDRMDLEEPEKVDKLQEPLLEA LRLYARRRRPSQPYMFPRMLMKITDLRGISTKGAERAITLKMEIPGPMPPLIREMLENPE MFEDDSSQPGPHPNASSEDEVPGGQGKGGLKSPA Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T80D9C |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 5 Approved Drugs | + | ||||
1 | Alitretinoin | Drug Info | Approved | Kaposi sarcoma | [2], [3] | |
2 | Palovarotene | Drug Info | Approved | Fibrodysplasia ossificans progressiva | [4] | |
3 | Tazarotene | Drug Info | Approved | Psoriasis vulgaris | [3], [5] | |
4 | Tretinoin | Drug Info | Approved | Acne vulgaris | [3], [6] | |
5 | Trifarotene | Drug Info | Approved | Acne vulgaris | [7] | |
Mode of Action | [+] 5 Modes of Action | + | ||||
Modulator | [+] 1 Modulator drugs | + | ||||
1 | Alitretinoin | Drug Info | [8], [9], [10] | |||
Agonist | [+] 12 Agonist drugs | + | ||||
1 | Palovarotene | Drug Info | [4] | |||
2 | Tretinoin | Drug Info | [9] | |||
3 | Trifarotene | Drug Info | [7] | |||
4 | PMID27336223-Compound-11 | Drug Info | [11] | |||
5 | PMID27336223-Compound-12 | Drug Info | [11] | |||
6 | PMID27336223-Compound-13 | Drug Info | [11] | |||
7 | PMID27336223-Compound-14 | Drug Info | [11] | |||
8 | PMID27336223-Compound-15 | Drug Info | [11] | |||
9 | PMID27336223-Compound-9 | Drug Info | [11] | |||
10 | AHPN | Drug Info | [13] | |||
11 | BMS270394 | Drug Info | [15] | |||
12 | CD666 | Drug Info | [17] | |||
Binder | [+] 1 Binder drugs | + | ||||
1 | Tazarotene | Drug Info | [1] | |||
Antagonist | [+] 3 Antagonist drugs | + | ||||
1 | AGN193109 | Drug Info | [12] | |||
2 | CD2665 | Drug Info | [16] | |||
3 | MM 11253 | Drug Info | [19] | |||
Inhibitor | [+] 4 Inhibitor drugs | + | ||||
1 | BMS184394 | Drug Info | [14] | |||
2 | CD564 | Drug Info | [14] | |||
3 | Dodecyl-Alpha-D-Maltoside | Drug Info | [18] | |||
4 | SR11254 | Drug Info | [14] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Binding Sites of Target | Top | |||||
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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 | No | [20] |
PDB Sequence |
LSPQLEELIT
191 KVSKAHQETF201 PSLCQLGKYT211 TNSSADHRVQ221 LDLGLWDKFS231 ELATKCIIKI 241 VEFAKRLPGF251 TGLSIADQIT261 LLKAACLDIL271 MLRICTRYTP281 EQDTMTFSDG 291 LTLNRTQMHN301 AGFGPLTDLV311 FAFAGQLLPL321 EMDDTETGLL331 SAICLICGDR 341 MDLEEPEKVD351 KLQEPLLEAL361 RLYARRRRPS371 QPYMFPRMLM381 KITDLRGIST 391 KGAERAITLK401 MEIPGPMPPL411 IREMLENP
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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
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Ligand Name: Alitretinoin | Ligand Info | |||||
Structure Description | RARg mutant-S371E | PDB:5M24 | ||||
Method | X-ray diffraction | Resolution | 1.69 Å | Mutation | Yes | [21] |
PDB Sequence |
LSPQLEELIT
191 KVSKAHQETF201 PSLCQLGKYT211 TNSSADHRVQ221 LDLGLWDKFS231 ELATKCIIKI 241 VEFAKRLPGF251 TGLSIADQIT261 LLKAACLDIL271 MLRICTRYTP281 EQDTMTFSDG 291 LTLNRTQMHN301 AGFGPLTDLV311 FAFAGQLLPL321 EMDDTETGLL331 SAICLICGDR 341 MDLEEPEKVD351 KLQEPLLEAL361 RLYARRRRPE371 QPYMFPRMLM381 KITDLRGIST 391 KGAERAITLK401 MEIPGPMPPL411 IREMLE
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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
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Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
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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
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There is no similarity protein (E value < 0.005) for this target
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Degree | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 1.15E-06 |
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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 | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"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 | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-regulating Transcription Factors | ||||||
Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target Affiliated Biological Pathways | Top | |||||
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Reactome | [+] 1 Reactome Pathways | + | ||||
1 | Nuclear Receptor transcription pathway | |||||
WikiPathways | [+] 5 WikiPathways | + | ||||
1 | Vitamin A and Carotenoid Metabolism | |||||
2 | Nuclear Receptors in Lipid Metabolism and Toxicity | |||||
3 | Mesodermal Commitment Pathway | |||||
4 | Endoderm Differentiation | |||||
5 | Nuclear Receptors |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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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 | 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: 6952). | |||||
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. (Ligand id: 2644). | |||||
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 | Induction of apoptosis by retinoids and retinoic acid receptor gamma-selective compounds in mouse thymocytes through a novel apoptosis pathway. Mol Pharmacol. 1997 Jun;51(6):972-82. | |||||
REF 17 | 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 18 | DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41. | |||||
REF 19 | 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 20 | Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature. 1995 Dec 14;378(6558):681-9. | |||||
REF 21 | Allosteric Regulation in the Ligand Binding Domain of Retinoic Acid ReceptorGamma. PLoS One. 2017 Jan 26;12(1):e0171043. |
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