Rational design of RAR-selective ligands revealed by RARβ crystal stucture

Abstract

The crystal structure of the ligand-binding domain of RARβ, 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 RARβ to bind more bulky agonists. Accordingly, we identified a ligand that shows RARβ selectivity with a 100-fold higher affinity to RARβ than to α or γ 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 RARα, γ antagonist and an RARβ agonist. In addition, we demonstrate how to generate an RARβ antagonist by gradually modifying the bulkiness of a single substitution. Together, our results provide structural guidelines for the synthesis of RARβ-selective agonists and antagonists, allowing for the first time to address pharmacologically the tumour suppressor role of RARβ in vitro and in animal models.