2zy0

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Crystal structure of the human RXR alpha ligand binding domain bound to a synthetic agonist compound and a coactivator peptide

Structural highlights

2zy0 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.9Å
Ligands:21P
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RXRA_HUMAN 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. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. 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 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.[1] [2] [3] [4]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

C/Si switch: Twofold sila-substitution (C/Si exchange) in the RXR-selective retinoids 4 a (SR11237) and 5 a leads to 4 b (disila-SR11237) and 5 b, respectively. Chemistry and biology of the C/Si pairs are reported.SR11237 (BMS649, 4 a) is a pan-RXR-selective retinoid agonist. Its silicon analogue, disila-SR11237 (4 b; twofold C/Si exchange), was prepared in a multistep synthesis by starting from 1,2-bis(ethynyldimethylsilyl)ethane. In addition, the related C/Si analogues 5 a and 5 b, with an indane (disila-indane) instead of a tetraline (disila-tetraline) skeleton, were synthesized. The C/Si pairs 4 a/4 b and 5 a/5 b were studied for their interaction with retinoid receptors and were demonstrated to be highly potent RXR-selective ("rexinoid") agonists. Interestingly, twofold C/Si exchange in the indane moiety of 5 a resulted in a 10-fold increase in biological activity of the corresponding silicon-containing rexinoid 5 b, possibly resulting from an increased receptor affinity or a divergent allosteric effect on co-regulator-binding surfaces. The crystal structures of the ternary complexes formed by 5 a and 5 b, respectively, with the ligand-binding domain of hRXRalpha and a peptide of the co-activator TIF2/GRIP1 revealed additional interactions of the disila analogue 5 b with the H7 and H11 residues, supporting the first option of increased binding affinity. This is the first demonstration of an increase in binding affinity of a ligand to a nuclear receptor by C/Si replacement, thereby adding this C/Si switch strategy to the repertoire of nuclear receptor ligand design.

Silicon analogues of the RXR-selective retinoid agonist SR11237 (BMS649): chemistry and biology.,Lippert WP, Burschka C, Gotz K, Kaupp M, Ivanova D, Gaudon C, Sato Y, Antony P, Rochel N, Moras D, Gronemeyer H, Tacke R ChemMedChem. 2009 Jul;4(7):1143-52. PMID:19496083[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Gorla-Bajszczak A, Juge-Aubry C, Pernin A, Burger AG, Meier CA. Conserved amino acids in the ligand-binding and tau(i) domains of the peroxisome proliferator-activated receptor alpha are necessary for heterodimerization with RXR. Mol Cell Endocrinol. 1999 Jan 25;147(1-2):37-47. PMID:10195690
  2. ↑ Harish S, Ashok MS, Khanam T, Rangarajan PN. Serine 27, a human retinoid X receptor alpha residue, phosphorylated by protein kinase A is essential for cyclicAMP-mediated downregulation of RXRalpha function. Biochem Biophys Res Commun. 2000 Dec 29;279(3):853-7. PMID:11162439 doi:10.1006/bbrc.2000.4043
  3. ↑ Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, Shintani Y, Fujie H, Matsuura Y, Koike K, Miyamura T. Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology. 2002 Apr;35(4):937-46. PMID:11915042 doi:10.1053/jhep.2002.32470
  4. ↑ Santos NC, Kim KH. Activity of retinoic acid receptor-alpha is directly regulated at its protein kinase A sites in response to follicle-stimulating hormone signaling. Endocrinology. 2010 May;151(5):2361-72. doi: 10.1210/en.2009-1338. Epub 2010 Mar , 9. PMID:20215566 doi:10.1210/en.2009-1338
  5. ↑ Lippert WP, Burschka C, Gotz K, Kaupp M, Ivanova D, Gaudon C, Sato Y, Antony P, Rochel N, Moras D, Gronemeyer H, Tacke R. Silicon analogues of the RXR-selective retinoid agonist SR11237 (BMS649): chemistry and biology. ChemMedChem. 2009 Jul;4(7):1143-52. PMID:19496083 doi:10.1002/cmdc.200900090

Contents


PDB ID 2zy0

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