Differing Membrane Interactions of Two Highly Similar Drug-Metabolizing Cytochrome P450 Isoforms: CYP 2C9 and CYP 2C19

被引:10
|
作者
Mustafa, Ghulam [1 ,2 ]
Nandekar, Prajwal P. [1 ,2 ]
Bruce, Neil J. [1 ]
Wade, Rebecca C. [1 ,2 ,3 ]
机构
[1] HITS, Mol & Cellular Modeling Grp, D-69118 Heidelberg, Germany
[2] Heidelberg Univ, Zentrum Mol Biol, DKFZ ZMBH Alliance, D-69120 Heidelberg, Germany
[3] Heidelberg Univ, Interdisciplinary Ctr Sci Comp IWR, D-69120 Heidelberg, Germany
关键词
cytochrome P450; isoform; membrane protein; protein-membrane interactions; enzyme substrate specificity; mutagenesis; molecular dynamics simulation; MICROSOMAL CYTOCHROME-P450; CLOPIDOGREL BIOACTIVATION; SUBSTRATE RECOGNITION; MOLECULAR-DYNAMICS; BINDING; IDENTIFICATION; RESIDUES; DETERMINANTS; MECHANISM; BILAYER;
D O I
10.3390/ijms20184328
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
The human cytochrome P450 (CYP) 2C9 and 2C19 enzymes are two highly similar isoforms with key roles in drug metabolism. They are anchored to the endoplasmic reticulum membrane by their N-terminal transmembrane helix and interactions of their cytoplasmic globular domain with the membrane. However, their crystal structures were determined after N-terminal truncation and mutating residues in the globular domain that contact the membrane. Therefore, the CYP-membrane interactions are not structurally well-characterized and their dynamics and the influence of membrane interactions on CYP function are not well understood. We describe herein the modeling and simulation of CYP 2C9 and CYP 2C19 in a phospholipid bilayer. The simulations revealed that, despite high sequence conservation, the small sequence and structural differences between the two isoforms altered the interactions and orientations of the CYPs in the membrane bilayer. We identified residues (including K72, P73, and I99 in CYP 2C9 and E72, R73, and H99 in CYP 2C19) at the protein-membrane interface that contribute not only to the differing orientations adopted by the two isoforms in the membrane, but also to their differing substrate specificities by affecting the substrate access tunnels. Our findings provide a mechanistic interpretation of experimentally observed effects of mutagenesis on substrate selectivity.
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页数:23
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