Rational design of RAR-selective ligands revealed by RARbeta crystal stucture.
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.
Germain
Pierre
P
Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS/INSERM/ULP, BP 10142, 67404 Illkirch Cedex, CU de Strasbourg, France.
Kammerer
Sabrina
S
Pérez
Efrén
E
Peluso-Iltis
Carole
C
Tortolani
David
D
Zusi
F Christopher
FC
Starrett
John
J
Lapointe
Philippe
P
Daris
Jean-Paul
JP
Marinier
Anne
A
de Lera
Angel R
AR
Rochel
Natacha
N
Gronemeyer
Hinrich
H
D001665:Binding Sites; D019295:Computational Biology; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000097768:Retinoic Acid Receptor gamma
D008024:Ligands; D018168:Receptors, Retinoic Acid; D000097768:Retinoic Acid Receptor gamma; C082925:retinoic acid receptor beta