IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Département de Biologie et de Génomique Structurales, Centre National de la Recherche Scientifique, Institut National de la Santé de la Recherche Médicale, Université de Strasbourg, 1 rue Laurent Fries, Illkirch, France.
J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):84-7. doi: 10.1016/j.jsbmb.2010.04.008. Epub 2010 Apr 18.
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.
在维生素 D （VDR）核受体中，组氨酸 305 参与配体的锚定。VDR H305Q 突变是在表现遗传性维生素 D 抵抗性佝偻病（HVDRR）的患者中发现的。我们报道了人 VDR H305Q-配体结合域与 1α，25（OH）2D3 结合的晶体结构，分辨率为 1.8A。该蛋白质采用野生型配体结合 VDR 的活性构象。突变部位的局部构象灵活性削弱了 25-OH 与 Gln305 之间的氢键，从而解释了突变蛋白对骨化三醇亲和力降低的原因。该结构为设计更有效的治疗 HVDRR 的配体提供了合理的方法。
