title: Analysis of the complex formation, interaction and electron transfer pathway between the "open" conformation of NADPH-cytochrome P450 reductase and aromatase.
abstract: The complex structure of human aromatase (CYP19) and the open form of ΔTGEE mutant NADPH-cytochrome P450 reductase (mCPR) was constructed using template-based protein alignment method. Dynamic simulation of formed complex was performed on NAMD 2.9, in which CHARMm all 27_prot_lipid_na force field and an explicit TIP3P water solvent model were applied. The result showed mCPR in its open conformation could steadily combine with aromatase from the proximal face. Data analysis indicates hydrogen bonds and four salt bridges on the binding surface enhance the interaction between the two protein molecules. Amino acid, Lys108 plays a key role in aromatase activity through the formation of a salt bridge with Asp147 and two hydrogen bonds with Asp147 and Gln150 in mCPR. The optimal pathway for the first electron transfer from CPR to aromatase was revealed and calculated using HARLEM software. The rates for solvent mediated and non-solvent mediated electron transfer from FMNH2 to heme were determined as 1.04×10(6)s(-)(1) and 4.86×10(5)s(-)(1) respectively, which indicates the solvent water can facilitate the electron transfer from FMNH2 to heme. This study presents a novel strategy for the study of the protein-protein interactions based on the template-based protein alignment, which may help new aromtase development targeting the electron transfer between mCPR and aromatase.
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology (Tianjin University of Science & Technology), Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China. Electronic address: yjdai@126.com.
authors.forename: Yuejie
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Medicinal Chemistry, School of Environmental and Biological Sciences, Rutgers University, NJ 08901, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhen
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology (Tianjin University of Science & Technology), Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China. Electronic address: zhxl1966@hotmail.com.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology (Tianjin University of Science & Technology), Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology (Tianjin University of Science & Technology), Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
authors.forename: Shaodan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology (Tianjin University of Science & Technology), Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, School of Environmental and Biological Sciences, Rutgers University, NJ 08901, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Medicinal Chemistry, School of Environmental and Biological Sciences, Rutgers University, NJ 08901, USA; Department of Plant Biology and Pathology, School of Environmental and Biological Sciences, Rutgers University, NJ 08901, USA.
authors.forename: Qingli
authors.initials: Q
authors.lastname: Wu
mesh_terms: D001141:Aromatase / Q000737:chemistry* / Q000378:metabolism*; D004579:Electron Transport; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009251:NADPH-Ferrihemoprotein Reductase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D001141:Aromatase; C561410:CYP19A1 protein, human; D009251:NADPH-Ferrihemoprotein Reductase
keywords: Alignment; Aromatase; Cytochrome P450 reductase; Electron transfer pathway; Molecular dynamics