Structural features and dynamic investigations of the membrane-bound cytochrome P450 17A1
Cytochrome P450(CYP)17A1 is a dual-function monooxygenase with a critical role in the synthesis or many human steroid hormones The enzyme is an important target for Lrealment of breast and prostate cancers that proliferate in response to estrogens and androgens.Despite the cryslallographic 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 gale formed by Trp220 and Phe224 are suggested to regulate tunnel opening motions.The knowledge of the membrane binding charactcristics could guide futureex pcrimcnlal and computational works on membrane-bound CYPs so that various investigations of CYPs in their natural,lipid environment rather than in artificially solttbilized forms may be achieved.
Molecular dynamic Cytochrome P450 Membrane-bound Access tunnel
Ying-Lu Cui Qiao Xue Qing-Chuan Zheng Ji-LongZhang Chui-Peng Kong Jing-Rong Fan Hong-Xing Zhang
International Joint Research Laboratory of Nana-micro Architecture Chemistry,State Key Laboratory of International Joint Research Laboratory of Nana-micro Architecture Chemistry,State Key Laboratory of International Joint Research Laboratory of Nana-micro Architecture Chemistry,State Key Laboratory of
国内会议
大连
英文
733-741
2016-09-24（万方平台首次上网日期，不代表论文的发表时间）