Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations

被引:15
|
作者
Oostenbrink, Chris [1 ,2 ]
de Ruiter, Anita [1 ]
Hritz, Jozef [3 ]
Vermeulen, Nico [2 ]
机构
[1] Univ Nat Resources & Life Sci, Inst Mol Modeling & Simulat, A-1190 Vienna, Austria
[2] Leiden Amsterdam Ctr Drug Res, Div Mol & Computat Toxicol, NL-1081 HV Amsterdam, Netherlands
[3] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA
基金
欧洲研究理事会;
关键词
Site of metabolism prediction; protein flexibility; molecular docking; molecular dynamics simulations; replica exchange; BINDING-AFFINITY; FREE-ENERGY; COMPUTATIONAL PREDICTION; SUBSTRATES ENTER; PRODUCTS EXIT; IN-SILICO; DYNAMICS; METABOLISM; P450; 2D6;
D O I
10.2174/138920012798918453
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
As the most important phase I drug metabolizing enzymes, the human Cytochromes P450 display an enormous versatility in the molecular structures of possible substrates. Individual isoforms may preferentially bind specific classes of molecules, but also within these classes, some isoforms show remarkable levels of promiscuity. In this work, we try to link this promiscuity to the versatility and malleability of the active site at the hand of examples from our own work. Mainly focusing on the flexibility of protein structures and the presence or absence of water molecules, we establish molecular reasons for observed promiscuity, determine the relevant factors to take into account when predicting binding poses and rationalize the role of individual interactions in the process of ligand binding. A high level of active site flexibility does not only allow for the binding of a large variety of substrates and inhibitors, but also appears to be important to facilitate ligand binding and unbinding.
引用
收藏
页码:190 / 196
页数:7
相关论文
共 50 条
  • [21] Progress in cytochrome P450 active site modeling
    Kemp, CA
    Maréchal, JD
    Sutcliffe, MJ
    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2005, 433 (02) : 361 - 368
  • [22] Evaluation of atypical cytochrome P450 kinetics with two-substrate models: Evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites
    Korzekwa, KR
    Krishnamachary, N
    Shou, M
    Ogai, A
    Parise, RA
    Rettie, AE
    Gonzalez, FJ
    Tracy, TS
    BIOCHEMISTRY, 1998, 37 (12) : 4137 - 4147
  • [23] Measurement of cytochrome P450 and NADPH-cytochrome P450 reductase
    Guengerich, F. Peter
    Martin, Martha V.
    Sohl, Christal D.
    Cheng, Qian
    NATURE PROTOCOLS, 2009, 4 (09) : 1245 - 1251
  • [24] Interactions of cytochrome P450 2B4 with NADPH-cytochrome P450 reductase studied by fluorescent probe
    Davydov, DR
    Knyushko, TV
    Kanaeva, IP
    Koen, YM
    Samenkova, NF
    Archakov, AI
    Hoa, GHB
    BIOCHIMIE, 1996, 78 (8-9) : 734 - 743
  • [25] Coupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation
    Iijima, Mikuru
    Ohnuki, Jun
    Sato, Takato
    Sugishima, Masakazu
    Takanat, Mitsunori
    SCIENTIFIC REPORTS, 2019, 9 (1)
  • [26] Coupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation
    Mikuru Iijima
    Jun Ohnuki
    Takato Sato
    Masakazu Sugishima
    Mitsunori Takano
    Scientific Reports, 9
  • [27] 13C-Methyl isocyanide as an NMR probe for cytochrome P450 active sites
    Christopher R. McCullough
    Phani Kumar Pullela
    Sang-Choul Im
    Lucy Waskell
    Daniel S. Sem
    Journal of Biomolecular NMR, 2009, 43 : 171 - 178
  • [28] 13C-Methyl isocyanide as an NMR probe for cytochrome P450 active sites
    McCullough, Christopher R.
    Pullela, Phani Kumar
    Im, Sang-Choul
    Waskell, Lucy
    Sem, Daniel S.
    JOURNAL OF BIOMOLECULAR NMR, 2009, 43 (03) : 171 - 178
  • [29] Coupling of the Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation
    Iijima, Mikuru
    Ohnuki, Jun
    Sato, Takato
    Sugishima, Masakazu
    Takano, Mitsunori
    PROTEIN SCIENCE, 2018, 27 : 140 - 140
  • [30] Molecular aspects of brain aromatase cytochrome P450
    Lephart, ED
    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 1997, 61 (3-6): : 375 - 380