Crystal structure of hereditary vitamin D-resistant rickets--associated mutant H305Q of vitamin D nuclear receptor bound to its natural ligand.

Date publication

juillet 2010

Auteurs

Membres identifiés du Cancéropôle Est :
Dr MORAS Dino

Tous les auteurs :
Rochel N, Hourai S, Moras D

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/20403435

Résumé

In the nuclear receptor of vitamin D (VDR) histidine 305 participates to the anchoring of the ligand. The VDR H305Q mutation was identified in a patient who exhibited the hereditary vitamin D-resistant rickets (HVDRR). We report the crystal structure of human VDR H305Q-ligand binding domain bound to 1alpha,25(OH)2D3 solved at 1.8A resolution. The protein adopts the active conformation of the wild-type liganded VDR. A local conformational flexibility at the mutation site weakens the hydrogen bond between the 25-OH with Gln305, thus explaining the lower affinity of the mutant proteins for calcitriol. The structure provides the basis for a rational approach to the design of more potent ligands for the treatment of HVDRR.

Référence

J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):84-7