Crystal structure of CYP24A1, a mitochondrial cytochrome P450 involved in vitamin D metabolism.
Crystal structure of CYP24A1, a mitochondrial cytochrome P450 involved in vitamin D metabolism.
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DOI：
10.1016/j.jmb.2009.11.057
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发表时间：
2010-02-19
影响因子：
5.6
通讯作者：
Stout CD
中科院分区：
文献类型：
--
作者：
Annalora AJ;Goodin DB;Hong WX;Zhang Q;Johnson EF;Stout CD
细胞色素P450(CYP)24A1催化激素形式的维生素D的侧链氧化。细胞色素P45024A1的表达上调，以减弱与钙稳态和细胞生长过程相关的维生素D信号。通过对CYP24A1的结构了解，将极大地促进与维生素D缺乏相关的疾病治疗的发展。在此，我们报道了大鼠细胞色素P24A1在2.5？分辨率下的晶体结构。该结构显示出一个开放的裂隙，通向远端表面上的活性部位血红素修复体基团，这可能定义了底物进入活性部位的路径。裂隙的入口两侧是螺旋A‘和G’上保守的疏水残基，暗示着一种插入线粒体内膜的方式。提出了一个开放形式的1-α，25-(OH)2D3结合的对接模型，阐明了类固醇识别的结构决定因素，并验证了现有的同源模型的预测能力。对CYP24A1‘S近端表面的分析表明，肾上腺素识别的决定因素是来自K、K“和L螺旋的保守残基星座，这些残基与邻近的富含赖氨酸的环聚合，与氧化还原蛋白结合。总体而言，CYP24A1结构为理解线粒体P450中的膜插入、底物结合和氧化还原伙伴相互作用提供了第一个模板。
Cytochrome P450 (CYP) 24A1 catalyzes the side-chain oxidation of the hormonal form of vitamin D. Expression of CYP24A1 is up-regulated to attenuate vitamin-D signaling associated with calcium homeostasis and cellular growth processes. The development of therapeutics for disorders linked to vitamin D-insufficiency would be greatly facilitated by structural knowledge of CYP24A1. Here we report the crystal structure of rat CYP24A1 at 2.5 Å resolution. The structure exhibits an open cleft leading to the active site heme prosthetic group on the distal surface that is likely to define the path of substrate access into the active site. The entrance to the cleft is flanked by conserved hydrophobic residues on helices A′ and G′ suggesting a mode of insertion into the inner mitochondrial membrane. A docking model for 1α,25-(OH)2D3 binding in the open form of CYP24A1 is proposed that clarifies the structural determinants of secosteroid recognition and validates the predictive power of existing homology models of CYP24A1. Analysis of CYP24A1's proximal surface identifies the determinants of adrenodoxin recognition as a constellation of conserved residues from helices K, K″ and L that converge with an adjacent lysine-rich loop for binding the redox protein. Overall, the CYP24A1 structure provides the first template for understanding membrane insertion, substrate binding, and redox partner interaction in mitochondrial P450s.
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影响因子：
2.9
作者：
Haines, Donovan C.;Chen, Baozhi;Peterson, Julian A.
通讯作者：
Peterson, Julian A.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
2.9
作者：
Beilke, D;Weiss, R;Rüterjans, H
通讯作者：
Rüterjans, H
影响因子：
4.1
作者：
Bernhardt, Rita
通讯作者：
Bernhardt, Rita
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL