Crystal structure of a vitamin D3 analog, ZK203278, showing dissociated profile.
The plethora of actions of 1α,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/1α,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.
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de Santé et de Recherche Médicale (INSERM) U964/Centre National de Recherche Scientifique (CNRS) UMR 7104/Université de Strasbourg, 67404 Illkirch, France. rochel@igbmc.fr
Natacha
N
Rochel
Dino
D
Moras
D018360:Crystallography, X-Ray; D006639:Histidine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D018167:Receptors, Calcitriol; D013844:Thiazoles; C544428:ZK203278; D014807:Vitamin D; D006639:Histidine