A Minimal Functional Complex of Cytochrome P450 and FBD of Cytochrome P450 Reductase in Nanodiscs

Abstract

Structural interactions that enable electron transfer to cytochromeâ P450 (CYP450) from its redox partner CYP450â reductase (CPR) are a vital prerequisite for its catalytic mechanism. The first structural model for the membraneâ bound functional complex to reveal interactions between the fullâ 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 cytochromeâ b5 (cytâ b5), Argâ 125 on the Câ 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 proteinâ 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.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 Wirkâ und Fremdstoffen durch diverse mikrosomale CYPs in ihrem nativen Membranumfeld wird aufgeklärt.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144609/1/ange201802210.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144609/2/ange201802210-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144609/3/ange201802210_am.pd