F/G Region Rigidity is Inversely Correlated to Substrate Promiscuity of Human CYP Isoforms Involved in Metabolism

被引：7

作者：

Becker, Daniel ^{[1
]}

Bharatam, Prasad, V ^{[2
]}

Gohlke, Holger ^{[1
,3
,4
]}

机构：

[1] Heinrich Heine Univ Dusseldorf, Inst Pharmazeut & Med Chem, Math Nat Wissensc Fak, D-40225 Dusseldorf, Germany

[2] Natl Inst Pharmaceut Educ & Res NIPER, Dept Med Chem, Mohali 160062, Punjab, India

[3] Forschungszentrum Julich, John von Neumann Inst Comp NIC, Julich Supercomp Ctr JSC, Inst Biol Informat Proc IBI 7 Struct Biochem, D-52425 Julich, Germany

[4] Forschungszentrum Julich, Inst Bio & Geosci IBG 4 Bioinformat, D-52425 Julich, Germany

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2021年 / 61卷 / 08期

关键词：

HUMAN CYTOCHROMES P450; MOLECULAR-DYNAMICS; STRUCTURAL BASIS; FLEXIBILITY; PREDICTION; ENZYME; AMBER; (THERMO-)STABILITY; THERMOSTABILITY; IDENTIFICATION;

D O I：

10.1021/acs.jcim.1c00558

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Of 57 human cytochrome P450 (CYP) enzymes, 12 metabolize 90% of xenobiotics. To our knowledge, no study has addressed the relation between enzyme dynamics and substrate promiscuity for more than three CYPs. Here, we show by constraint dilution simulations with the Constraint Network Analysis for the 12 isoforms that structural rigidity of the F/G region is significantly inversely correlated to the enzymes' substrate promiscuity. This highlights the functional importance of structural dynamics of the substrate tunnel.

引用

页码：4023 / 4030

页数：8

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