Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARγ

Abstract

The human retinoic acid receptor (hRAR) is a member of the nuclear receptor superfamily that regulates the transcription of target genes in a ligand-dependent manner. The three hRAR isotypes are targets for retinoids that are used in the treatment of various diseases, including breast cancer and skin diseases. Drug efficiency and safety depend on the pharmacological activity of enantiomers, which can differ because of the chiral environment generated by the target. We report the crystal structures of the hRAR␥ ligandbinding domain bound to two enantiomers, the active BMS270394 and the inactive BMS270395, solved at 1.6 Å and 1.7 Å resolution, respectively. The crystal structures reveal that in both enantiomers, the hydroxyl moiety attached to the chiral center forms a hydrogen bond to the Met-272 sulfur atom, thus imposing a conformation of BMS270395 that differs significantly from that observed for BMS270394 and other known retinoids. BMS270395 adopts an energetically unfavorable conformation, accounting for its inactivity; in contrast, the conformation of BMS270394 is close to an energy minimum. Our high-resolution data allow rationalization of enantiomer discrimination by the receptor and provide a model system for the pharmacological properties of enantiomeric pairs.

Crystal structures of the vitamin D receptor complexed to superagonist 20-epi ligands

“…The protein structures are identical to that observed in the complex with the natural ligand. A similar observation has already been made for retinoic acid receptor, where numerous complexes with the two natural ligands (all-trans-and 9-cis-retinoic acid) and synthetic analogs revealed that the ligand-binding pocket was unchanged and that it is the ligand that adapts (26)(27)(28)(29). Such observations should be valid not only for retinoic acid receptor and VDR but most likely also for other NRs.…”

Dual RXR Agonists and RAR Antagonists Based on the Stilbene Retinoid Scaffold

“…26−30 Numerous modifications of the basic scaffold have been systematically carried out in order to correlate structure and functional consequences of retinoid ligand modifications on receptor activation. 17−19 Substitution at the naphthalene C8 position afford in general ligands with RAR antagonist/inverse agonist activities, 28−30 and this is modulated 31 by synergy with halogen atoms at the C3 position 32 of the benzoic acid terminus. In these structures, the LBP volume around the naphthalene C5 position is filled with a hydrophobic gemdimethyl group.…”

“…Ligand 11a was positioned in the active site on the basis of the canonical positions revealed by the crystal structures. [20][21][22]32,43,44 Preferred docking sites for functional groups were evaluated with the program GRID, 45 which assisted in the selection of binding modes. 31 The resulting model showed the two phenyl moieties at C5 and C8 positions running almost perpendicular to the ethenylbenzoic acid buried in a predominantly hydrophobic pocket (Figure 4).…”

A Novel Molecular Target for Breast Cancer Prevention and Treatment

“…Energy-minimized conformers of AHPN [1], RAR-selective trans-RA [3], and RAR-selective TTAB [5] (39) were overlapped. The trans-RA conformer was that reported in the RARy LBD (40,41). Three orthogonal views of these overlaps are shown in Fig.…”