Crystal structure of a vitamin D3 analog, ZK203278, showing dissociated profile.
Fiche publication
Date publication
janvier 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MORAS Dino, Dr ROCHEL-GUIBERTEAU Natacha
Tous les auteurs :
Rochel N, Moras D
Lien Pubmed
Résumé
The plethora of actions of 1alpha,25-dihydroxyvitamin D(3), the active form of the seco-steroid hormone vitamin D, in various systems suggested wide clinical applications in treatments for renal osteodystrophy, osteoporosis, psoriasis, cancer, autoimmune diseases and prevention of graft rejection. However, the major side-effects of hypercalcemia of VDR ligands limit their use. ZK203278, a novel synthetic analog has been shown to act as a potent immunomodulator and presents dissociated biologic profile with low calcemic side-effects. Here, we described the crystal structures of the hVDR ligand-binding domain in complex with ZK203278 and determined its correlation with its specific dissociated biologic profile. The VDR/ZK203278 structure, in comparison with VDR/1alpha,25-dihydroxyvitamin D(3), shows specific interactions of the thiazole group of ZK203278 with residues of H3, H11 and H12. These specific interactions may lead to altered selective interactions with co-regulators and consequently to the dissociated biologic profile of this novel ligand.
Référence
Anticancer Res. 2012 Jan;32(1):335-9.