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

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• 作者：Natacha Rochel ; Shinji Hourai ; Dino Moras
• 关键词：VDR mutant rickets ; Calcitriol ; Crystal structure
• 刊名：The Journal of Steroid Biochemistry and Molecular Biology
• 出版年：2010
• 出版时间：July 2010
• 年：2010
• 卷：121
• 期：1-2
• 页码：84-87
• 全文大小：414 K

文摘

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 1α,25(OH)₂D₃ solved at 1.8 Å 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.