Structural analysis of CYP2R1 in complex with vitamin D3
Structural analysis of CYP2R1 in complex with vitamin D3
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DOI：
10.1016/j.jmb.2008.03.065
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发表时间：
2008-06-27
影响因子：
5.6
通讯作者：
Park, Hee-Won
中科院分区：
文献类型：
--
作者：
Strushkevich, Naltallia;Usanov, Serge A.;Park, Hee-Won
维生素D的激素活化是由细胞色素P450酶介导的。CYP2R1催化维生素D转化为25-羟基维生素D的第一步。由于缺乏25-羟基酶，CYP2R1基因突变会导致遗传性软骨病。为了了解CYP2R1的窄底物特异性，我们在高纯度状态下获得了血红蛋白，证实了该酶为维生素D25-羟基酶，并解析了该酶与维生素D-3形成的复合体的晶体结构。该结构采用封闭构象，底物进入通道被有序的B‘-螺旋覆盖，并向表面略微开放，这定义了底物入口点。活性部位由保守的，主要是疏水残基排列。维生素D3以拉长的构象结合，脂肪族侧链指向血红素。该结构揭示了延伸的活性部位中的Secosterid结合模式，并使与CYP2R1相关的遗传性软骨病的分子基础合理化。(C)2008爱思唯尔有限公司。保留所有权利。
The activation of vitamin D to its hormonal form is mediated by cytochrome P450 enzymes. CYP2R1 catalyzes the initial step converting vitamin D into 25-hydroxyvitamin D. A CYP2R1 gene mutation causes an inherited form of rickets due to 25-hydroxylase deficiency. To understand the narrow substrate specificity of CYP2R1 we obtained the hemeprotein in a highly purified state, confirmed the enzyme as a vitamin D 25-hydroxylase, and solved the crystal structure of CYP2R1 in complex with vitamin D-3. The CYP2R1 structure adopts a closed conformation with the substrate access channel being covered by the ordered B'-helix and slightly opened to the surface, which defines the substrate entrance point. The active site is lined by conserved, mostly hydrophobic residues. Vitamin D3 is bound in an elongated conformation with the aliphatic side-chain pointing toward the heme. The structure reveals the secosteroid binding mode in an extended active site and allows rationalization of the molecular basis of the inherited rickets associated with CYP2R1. (C) 2008 Elsevier Ltd. All rights reserved.