Target Information

Target General Information

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Target ID

T13726 (Former ID: TTDR01073)

Target Name

Retinoic acid receptor RXR-alpha (RXRA)

Synonyms

Retinoid X receptor alpha; RXRalpha; Nuclear receptor subfamily 2 group B member 1; NR2B1

Gene Name

RXRA

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Kaposi sarcoma [ICD-11: 2B57]

Mycosis fungoides [ICD-11: 2B01]

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 RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes. Receptor for retinoic acid.

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BioChemical Class

Nuclear hormone receptor

UniProt ID

RXRA_HUMAN

Sequence

MDTKHFLPLDFSTQVNSSLTSPTGRGSMAAPSLHPSLGPGIGSPGQLHSPISTLSSPING
MGPPFSVISSPMGPHSMSVPTTPTLGFSTGSPQLSSPMNPVSSSEDIKPPLGLNGVLKVP
AHPSGNMASFTKHICAICGDRSSGKHYGVYSCEGCKGFFKRTVRKDLTYTCRDNKDCLID
KRQRNRCQYCRYQKCLAMGMKREAVQEERQRGKDRNENEVESTSSANEDMPVERILEAEL
AVEPKTETYVEANMGLNPSSPNDPVTNICQAADKQLFTLVEWAKRIPHFSELPLDDQVIL
LRAGWNELLIASFSHRSIAVKDGILLATGLHVHRNSAHSAGVGAIFDRVLTELVSKMRDM
QMDKTELGCLRAIVLFNPDSKGLSNPAEVEALREKVYASLEAYCKHKYPEQPGRFAKLLL
RLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLEAPHQMT

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3D Structure

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PDB

ADReCS ID

BADD_A02162 ; BADD_A02367 ; BADD_A02556 ; BADD_A04820 ; BADD_A06050 ; BADD_A06355 ; BADD_A06560

HIT2.0 ID

T45XTW

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Alitretinoin

Drug Info

Approved

Kaposi sarcoma

[2], [3]

Bexarotene

Drug Info

Approved

Cutaneous T-cell lymphoma

[4], [5]

Mode of Action

[+] 4 Modes of Action

Agonist

[+] 4 Agonist drugs

Alitretinoin

Drug Info

[1]

CD3254

Drug Info

[9]

methoprene acid

Drug Info

[11]

phytanic acid

Drug Info

[13]

Modulator

[+] 1 Modulator drugs

Bexarotene

Drug Info

[6]

Inhibitor

[+] 4 Inhibitor drugs

(5BETA)-PREGNANE-3,20-DIONE

Drug Info

[7]

2-chloro-5-nitro-N-phenylbenzamide

Drug Info

[7]

AGN-34

Drug Info

[8]

Tributylstannanyl

Drug Info

[7]

Antagonist

[+] 3 Antagonist drugs

LG100754

Drug Info

[10]

PA451

Drug Info

[12]

UVI3003

Drug Info

[14]

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-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 12 KEGG Pathways	+
1	PPAR signaling pathway
2	PI3K-Akt signaling pathway
3	Thyroid hormone signaling pathway
4	Adipocytokine signaling pathway
5	Non-alcoholic fatty liver disease (NAFLD)
6	Bile secretion
7	Hepatitis C
8	Pathways in cancer
9	Transcriptional misregulation in cancer
10	Thyroid cancer
11	Small cell lung cancer
12	Non-small cell lung cancer
Panther Pathway	[+] 1 Panther Pathways	+
1	Vitamin D metabolism and pathway
PID Pathway	[+] 4 PID Pathways	+
1	Regulation of Androgen receptor activity
2	RXR and RAR heterodimerization with other nuclear receptor
3	Retinoic acid receptors-mediated signaling
4	a6b1 and a6b4 Integrin signaling
Reactome	[+] 14 Reactome Pathways	+
1	RORA activates gene expression
2	BMAL1:CLOCK,NPAS2 activates circadian gene expression
3	Recycling of bile acids and salts
4	PPARA activates gene expression
5	Import of palmitoyl-CoA into the mitochondrial matrix
6	YAP1- and WWTR1 (TAZ)-stimulated gene expression
7	Regulation of pyruvate dehydrogenase (PDH) complex
8	Endogenous sterols
9	Transcriptional activation of mitochondrial biogenesis
10	Activation of gene expression by SREBF (SREBP)
11	Transcriptional regulation of white adipocyte differentiation
12	Nuclear Receptor transcription pathway
13	Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)
14	Circadian Clock
WikiPathways	[+] 18 WikiPathways	+
1	Vitamin A and Carotenoid Metabolism
2	NRF2 pathway
3	Nuclear Receptors Meta-Pathway
4	Farnesoid X Receptor Pathway
5	PPAR Alpha Pathway
6	Vitamin D Receptor Pathway
7	Pregnane X Receptor pathway
8	Constitutive Androstane Receptor Pathway
9	Liver X Receptor Pathway
10	Regulation of Lipid Metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)
11	Transcriptional Regulation of White Adipocyte Differentiation
12	YAP1- and WWTR1 (TAZ)-stimulated gene expression
13	Activation of Gene Expression by SREBP (SREBF)
14	Integrated Pancreatic Cancer Pathway
15	Adipogenesis
16	Circadian Clock
17	Nuclear Receptors
18	Vitamin D Metabolism

Target-Related Models and Studies

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Target Validation

Target Validation Info

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

REF 5

Emerging drugs in cutaneous T cell lymphoma. Expert Opin Emerg Drugs. 2008 Jun;13(2):345-61.

REF 6

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

REF 7

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 8

Farnesoid X receptor: from structure to potential clinical applications. J Med Chem. 2005 Aug 25;48(17):5383-403.

REF 9

Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature. 2002 Jan 10;415(6868):187-92.

REF 10

The rexinoid LG100754 is a novel RXR:PPARgamma agonist and decreases glucose levels in vivo. Mol Endocrinol. 2001 Aug;15(8):1360-9.

REF 11

Activation of mammalian retinoid X receptors by the insect growth regulator methoprene. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):6157-60.

REF 12

Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimer actions. J Med Chem. 2002 Aug 1;45(16):3327-30.

REF 13

Phytanic acid is a retinoid X receptor ligand. Eur J Biochem. 1996 Feb 15;236(1):328-33.

REF 14

Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators thro... J Biol Chem. 2005 Jan 14;280(2):1625-33.

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