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

Natacha Rochel (1, 2) , Shinji Hourai , Dino Moras (1, 2)

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
2 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

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.

Domaines: Biochimie, Biologie Moléculaire

Natacha Rochel, Shinji Hourai, Dino Moras. Crystal structure of hereditary vitamin D-resistant rickets--associated mutant H305Q of vitamin D nuclear receptor bound to its natural ligand. Journal of Steroid Biochemistry and Molecular Biology, 2010, 121 (1-2), pp.84-87. ⟨10.1016/j.jsbmb.2010.04.008⟩. ⟨hal-04014329⟩