1fcx

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spinqualitylabelsall models 1fcx, resolution 1.47Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

ISOTYPE SELECTIVITY OF THE HUMAN RETINOIC ACID NUCLEAR RECEPTOR HRAR: THE COMPLEX WITH THE RARGAMMA-SELECTIVE RETINOID BMS184394

Overview

The human retinoic acid receptor (hRAR) belongs to the family of nuclear, receptors that regulate transcription in a ligand-dependent way. The, isotypes RARalpha,beta and gamma are distinct pharmacological targets for, retinoids that are involved in the treatment of various skin diseases and, cancers, in particular breast cancer and acute promyelocytic leukemia., Therefore, synthetic retinoids have been developed aiming at isotype, selectivity and reduced side-effects. We report the crystal structures of, three complexes of the hRARgamma ligand-binding domain (LBD) bound to, agonist retinoids that possess selectivity either for RARgamma (BMS184394), or for RARbeta/gamma (CD564), or that are potent for all RAR-isotypes, (panagonist BMS181156). The high resolution data (1.3-1. 5 A) provide a, description at the atomic level of the ligand pocket revealing the, molecular determinants for the different degrees of ligand selectivity., The comparison of the complexes of the chemically closely related, retinoids BMS184394 and CD564 shows that the side-chain of Met272 adopts, different conformations depending on the presence of a hydrogen bond, between its sulfur atom and the ligand. This accounts for their different, isotype selectivity. On the other hand, the difference between the pan-, and the RARbeta, gamma-selective agonist is probably due to a steric, discrimination at the level of the 2-naphthoic acid moiety of CD564. Based, on this study, we propose a model for a complex with the RARgamma-specific, agonist CD666 that shows the possible applications for structure-based, drug design of RAR isotype-selective retinoids.

About this Structure

1FCX is a Single protein structure of sequence from Homo sapiens with 184 and LMU as ligands. Full crystallographic information is available from OCA.

Reference

Structural basis for isotype selectivity of the human retinoic acid nuclear receptor., Klaholz BP, Mitschler A, Moras D, J Mol Biol. 2000 Sep 8;302(1):155-70. PMID:10964567

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