Membrane-Anchored Cytochrome P450 1A2–Cytochrome b5 Complex Features an X-Shaped Contact between Antiparallel Transmembrane Helices

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• 作者：Petr Jeřábek ; Jan Florián ; Václav Martínek
• 刊名：Chemical Research in Toxicology
• 出版年：2016
• 出版时间：April 18, 2016
• 年：2016
• 卷：29
• 期：4
• 页码：626-636
• 全文大小：614K
• 年卷期：0
• ISSN：1520-5010

文摘

Eukaryotic cytochromes P450 (P450) are membrane-bound enzymes oxidizing a broad spectrum of hydrophobic substrates, including xenobiotics. Protein–protein interactions play a critical role in this process. In particular, the formation of transient complexes of P450 with another protein of the endoplasmic reticulum membrane, cytochrome b₅ (cyt b₅), dictates catalytic activities of several P450s. To lay a structural foundation for the investigation of these effects, we constructed a model of the membrane-bound full-length human P450 1A2–cyt b₅ complex. The model was assembled from several parts using a multiscale modeling approach covering all-atom and coarse-grained molecular dynamics (MD). For soluble P450 1A2–cyt b₅ complexes, these simulations yielded three stable binding modes (sA_I, sA_II, and sB). The membrane-spanning transmembrane domains were reconstituted with the phospholipid bilayer using self-assembly MD. The predicted full-length membrane-bound complexes (mA_I and mB) featured a spontaneously formed X-shaped contact between antiparallel transmembrane domains, whereas the mA_II mode was found to be unstable in the membrane environment. The mutual position of soluble domains in binding mode mA_I was analogous to the sA_I complex. Featuring the largest contact area, the least structural flexibility, the shortest electron transfer distance, and the highest number of interprotein salt bridges, mode mA_I is the best candidate for the catalytically relevant full-length complex.