title: Structural and dynamic basis of human cytochrome P450 7B1: a survey of substrate selectivity and major active site access channels.
abstract: Cytochrome P450 (CYP) 7B1 is a steroid cytochrome P450 7α-hydroxylase that has been linked directly with bile salt synthesis and hereditary spastic paraplegia type 5 (SPG5). The enzyme provides the primary metabolic route for neurosteroids dehydroepiandrosterone (DHEA), cholesterol derivatives 25-hydroxycholesterol (25-HOChol), and other steroids such as 5α-androstane-3β,17β-diol (anediol), and 5α-androstene-3β,17β-diol (enediol). A series of investigations including homology modeling, molecular dynamics (MD), and automatic docking, combined with the results of previous experimental site-directed mutagenesis studies and access channels analysis, have identified the structural features relevant to the substrate selectivity of CYP7B1. The results clearly identify the dominant access channels and critical residues responsible for ligand binding. Both binding free energy analysis and total interaction energy analysis are consistent with the experimental conclusion that 25-HOChol is the best substrate. According to 20 ns MD simulations, the Phe cluster residues that lie above the active site, particularly Phe489, are proposed to merge the active site with the adjacent channel to the surface and accommodate substrate binding in a reasonable orientation. The investigation of CYP7B1-substrate binding modes provides detailed insights into the poorly understood structural features of human CYP7B1 at the atomic level, and will be valuable information for drug development and protein engineering.
authors.affiliation: 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.forename: Ji-Long
authors.initials: JL
authors.lastname: Zhang
authors.forename: Qing-Chuan
authors.initials: QC
authors.lastname: Zheng
authors.forename: Rui-Juan
authors.initials: RJ
authors.lastname: Niu
authors.forename: Yu
authors.initials: Y
authors.lastname: Xu
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
authors.forename: Chia-Chung
authors.initials: CC
authors.lastname: Sun
mesh_terms: D020134:Catalytic Domain; D000072474:Cytochrome P450 Family 7; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D054852:Small Molecule Libraries / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D054852:Small Molecule Libraries; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human