Structural basis for isotype selectivity of the human retinoic acid nuclear receptor

• Published in: Journal of molecular biology 2000-09, Vol.302 (1), p.155-170
• Main Authors: Klaholz, B P, Mitschler, A, Moras, D
• Format: Article
• Language: English
• Subjects: Binding Sites; Crystallography, X-Ray; Drug Design; Humans; Hydrogen Bonding; Ligands; Models, Molecular; Protein Isoforms - agonists; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Protein Structure, Tertiary; Receptors, Retinoic Acid - agonists; Receptors, Retinoic Acid - chemistry; Receptors, Retinoic Acid - metabolism; Retinoic Acid Receptor gamma; Retinoids - chemistry; Retinoids - metabolism; Retinoids - pharmacology; Structure-Activity Relationship; Substrate Specificity
• ISSN: 0022-2836
• DOI: 10.1006/jmbi.2000.4032

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.