1FCX

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

Summary for 1FCX

• Entry DOI: 10.2210/pdb1fcx/pdb
• Related: 1EXA 1EXX 1fcy 1fcz 1fd0 2LBD 3LBD
• Descriptor: RETINOIC ACID RECEPTOR GAMMA-1, 6-[HYDROXY-(5,5,8,8-TETRAMETHYL-5,6,7,8-TETRAHYDRO-NAPHTALEN-2-YL)-METHYL]-NAPHTALENE-2-CARBOXYLIC ACID, DODECYL-ALPHA-D-MALTOSIDE, ... (4 entities in total)
• Functional Keywords: isotype selectivity, retinoid ligand complexes, drug design, antiparallel alpha-helical sandwich fold, structural proteomics in europe, spine, structural genomics, gene regulation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 27434.18

Authors

Klaholz, B.P.,Mitschler, A.,Moras, D.,Structural Proteomics in Europe (SPINE) (deposition date: 2000-07-19, release date: 2000-09-11, Last modification date: 2023-08-09)

Primary citation

Klaholz, B.P.,Mitschler, A.,Moras, D.
Structural basis for isotype selectivity of the human retinoic acid nuclear receptor.
J.Mol.Biol., 302:155-170, 2000

PubMed Abstract: 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.

PubMed: 10964567
DOI: 10.1006/jmbi.2000.4032

Experimental method

X-RAY DIFFRACTION (1.47 Å)