Rational design of RAR-selective ligands revealed by RARbeta crystal stucture.

Abstract:

:The crystal structure of the ligand-binding domain of RARbeta, a suspect tumour suppressor, reveals important features that distinguish it from the two other RAR isotypes. The most striking difference is an extra cavity allowing RARbeta to bind more bulky agonists. Accordingly, we identified a ligand that shows RARbeta selectivity with a 100-fold higher affinity to RARbeta than to alpha or gamma isotypes. The structural differences between the three RAR ligand-binding pockets revealed a rationale explaining how a single retinoid can be at the same time an RARalpha, gamma antagonist and an RARbeta agonist. In addition, we demonstrate how to generate an RARbeta antagonist by gradually modifying the bulkiness of a single substitution. Together, our results provide structural guidelines for the synthesis of RARbeta-selective agonists and antagonists, allowing for the first time to address pharmacologically the tumour suppressor role of RARbeta in vitro and in animal models.

journal_name

EMBO Rep

journal_title

EMBO reports

authors

Germain P,Kammerer S,Pérez E,Peluso-Iltis C,Tortolani D,Zusi FC,Starrett J,Lapointe P,Daris JP,Marinier A,de Lera AR,Rochel N,Gronemeyer H

doi

10.1038/sj.embor.7400235

keywords:

subject

Has Abstract

pub_date

2004-09-01 00:00:00

pages

877-82

issue

9

eissn

1469-221X

issn

1469-3178

pii

7400235

journal_volume

5

pub_type

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