A Minimal Functional Complex of Cytochrome P450 and FBD of Cytochrome P450 Reductase in Nanodiscs. (14th June 2018)

• Record Type: Journal Article
• Authors: Prade, Elke; Mahajan, Mukesh; Im, Sang‐Choul; Zhang, Meng; Gentry, Katherine A.; Anantharamaiah, G. M.; Waskell, Lucy; Ramamoorthy, Ayyalusamy
• Is Part Of: Angewandte Chemie. Volume 130:Number 28(2018)
• Page Start: 8594
• Page End: 8598
• Publication Date: 2018-06-14
• Subjects: Cytochrom P450 -- Cytochrom-P450-Reduktase -- Membranprotein -- Nanoscheiben; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201802210
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Structural interactions that enable electron transfer to cytochrome‐P450 (CYP450) from its redox partner CYP450‐reductase (CPR) are a vital prerequisite for its catalytic mechanism. The first structural model for the membrane‐bound functional complex to reveal interactions between the full‐length CYP450 and a minimal domain of CPR is now reported. The results suggest that anchorage of the proteins in a lipid bilayer is a minimal requirement for CYP450 catalytic function. Akin to cytochrome‐b5 (cyt‐b5 ), Arg 125 on the C‐helix of CYP450s is found to be important for effective electron transfer, thus supporting the competitive behavior of redox partners for CYP450s. A general approach is presented to study protein–protein interactions combining the use of nanodiscs with NMR spectroscopy and SAXS. Linking structural details to the mechanism will help unravel the xenobiotic metabolism of diverse microsomal CYP450s in their native environment and facilitate the design of new drug entities. Abstract : Auf der Grundlage einer Strukturanalyse von Cytochrom P450 (CYP450) im Komplex mit seinem Redoxpartner kann der Pfad des selektiven Elektronentransfers verstanden werden. Strukturelle Wechselwirkungen in einem solchen Komplex, verankert in einer Lipidmembran, sind eine Grundvoraussetzung für diese Funktion. Der Stoffwechsel von Wirk‐ und Fremdstoffen durch diverse mikrosomale CYPs in ihrem nativen Membranumfeld wird aufgeklärt.