Structural features and dynamic investigations of the membrane-bound cytochrome P450 17A1
Structural features and dynamic investigations of the membrane-bound cytochrome P450 17A1
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膜结合细胞色素P450 17A1的结构特征和动态研究
DOI：
10.1016/j.bbamem.2015.05.017
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发表时间：
2015-10-01
影响因子：
3.4
通讯作者：
Zhang, Hong-Xing
中科院分区：
文献类型：
--
作者：
Cui, Ying-Lu;Xue, Qiao;Zhang, Hong-Xing
细胞色素P450（CYP17）A1是一种双功能单加氧酶，在许多人类类固醇激素的合成中起关键作用。这种酶是治疗乳腺癌和前列腺癌的重要靶点，乳腺癌和前列腺癌对雌激素和雄激素有反应。尽管CYP17A1的晶体结构可用，但在原子水平上没有这种酶的膜结合结构特征。越来越多的证据表明，结合CYP和膜之间的相互作用可能有助于招募亲脂性底物。为此，我们研究了存在膜时对CYP17A1结构特征的影响。分子动力学模拟的结果表明，一个自发插入过程的酶的脂质。CYP17A1在膜中的两种主要模式被捕获，其特征在于插入的深度和酶对膜表面的取向。血红素倾斜角的测量结果与实验数据吻合较好，从而验证了结构模型的有效性。此外，由膜诱导的构象变化可能会影响活性位点对亲脂性底物的可及性。由Trp220和Phe224形成的内部芳香门的动力学被建议调节隧道打开运动。膜结合特性的知识可以指导未来的实验和计算工作的膜结合CYP，使各种调查的CYP在其自然的，脂质环境，而不是在人工增溶的形式可以实现。(C)2015年由Elsevier B.V.出版
Cytochrome P450 (CYP) 17A1 is a dual-function monooxygenase with a critical role in the synthesis of many human steroid hormones. The enzyme is an important target for treatment of breast and prostate cancers that proliferate in response to estrogens and androgens. Despite the crystallographic structures available for CYP17A1, no membrane-bound structural features of this enzyme at atomic level are available. Accumulating evidence has indicated that the interactions between bounded CYPs and membrane could contribute to the recruitment of lipophilic substrates. To this end, we have investigated the effects on structural characteristics in the presence of the membrane for CYP17A1. The MD simulation results demonstrate a spontaneous insertion process of the enzyme to the lipid. Two predominant modes of CYP17A1 in the membrane are captured, characterized by the depths of insertion and orientations of the enzyme to the membrane surface. The measured heme tilt angles show good consistence with experimental data, thereby verifying the validity of the structural models. Moreover, conformational changes induced by the membrane might have impact on the accessibility of the active site to lipophilic substrates. The dynamics of internal aromatic gate formed by Trp220 and Phe224 are suggested to regulate tunnel opening motions. The knowledge of the membrane binding characteristics could guide future experimental and computational works on membrane-bound CYPs so that various investigations of CYPs in their natural, lipid environment rather than in artificially solubilized forms may be achieved. (C) 2015 Published by Elsevier B.V.