title: Structural features and dynamic investigations of the membrane-bound cytochrome P450 17A1.
abstract: 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.
authors.affiliation: International Joint Research Laboratory of Nano-micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, PR China.
authors.forename: Ying-Lu
authors.initials: YL
authors.lastname: Cui
authors.affiliation: International Joint Research Laboratory of Nano-micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, PR China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 10085, PR China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Xue
authors.affiliation: International Joint Research Laboratory of Nano-micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, PR China; Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130023, PR China. Electronic address: zhengqc@jlu.edu.cn.
authors.forename: Qing-Chuan
authors.initials: QC
authors.lastname: Zheng
authors.affiliation: International Joint Research Laboratory of Nano-micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, PR China.
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Zhang
authors.affiliation: International Joint Research Laboratory of Nano-micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, PR China.
authors.forename: Chui-Peng
authors.initials: CP
authors.lastname: Kong
authors.affiliation: International Joint Research Laboratory of Nano-micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, PR China.
authors.forename: Jing-Rong
authors.initials: JR
authors.lastname: Fan
authors.affiliation: International Joint Research Laboratory of Nano-micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, PR China.
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D008051:Lipid Bilayers / Q000737:chemistry*; D008560:Membrane Fluidity; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013254:Steroid 17-alpha-Hydroxylase / Q000737:chemistry* / Q000648:ultrastructure*
chemical_list: D008051:Lipid Bilayers; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase
keywords: Access tunnel; Cytochrome P450; Membrane-bound; Molecular dynamic