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

The human retinoic acid receptor (hRAR) belongs to the family of nuclear re ceptors that regulate transcription in a ligand-dependent way. The isotypes RAR alpha,beta and gamma are distinct pharmacological targets for retinoid s that are involved in the treatment of various skin diseases and cancers, in particular breast cancer and acute promyelocytic leukemia. Therefore, sy nthetic retinoids have been developed aiming at isotype selectivity and red uced side-effects. We report the crystal structures of three complexes of t he hRAR gamma ligand-binding domain (LBD) bound to agonist retinoids that p ossess selectivity either for RAR gamma (BMS184394) or for RAR beta/gamma ( CD564), or that are potent for all RAR-isotypes (panagonist BMS181156). The high resolution data (1.3-1.5 Angstrom) provide a description at the atomi c level of the ligand pocket revealing the molecular determinants for the d ifferent 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 prese nce of a hydrogen bond between its sulfur atom and the ligand. This account s for their different isotype selectivity. On the other hand, the differenc e between the pan- and the RAR beta,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 RAR g amma-specific agonist CD666 that shows the possible applications for struct ure-based drug design of RAR isotype-selective retinoids. (C) 2000 Academic Press.