Architecture of a single membrane spanning cytochrome P450 suggests constraints that orient the catalytic domain relative to a bilayer

Brian C. Monk, Thomas M. Tomasiak, Mikhail V. Keniya, Franziska U. Huschmann, Joel D A Tyndall, Joseph D. O'Connell, Richard D. Cannon, Jeffrey G. McDonald, Andrew Rodriguez, Janet S. Finer-Moore, Robert M. Stroud

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151 Scopus citations

Abstract

Bitopic integral membrane proteins with a single transmembrane helix play diverse roles in catalysis, cell signaling, and morphogenesis. Complete monospanning protein structures are needed to show how interaction between the transmembrane helix and catalytic domain might influence association with the membrane and function. We report crystal structures of full-length Saccharomyces cerevisiae lanosterol 14α-demethylase, a membrane monospanning cytochrome P450 of the CYP51 family that catalyzes the first postcyclization step in ergosterol biosynthesis and is inhibited by triazole drugs. The structures reveal a well-ordered N-terminal amphipathic helix preceding a putative transmembrane helix that would constrain the catalytic domain orientation to lie partly in the lipid bilayer. The structures locate the substrate lanosterol, identify putative substrate and product channels, and reveal constrained interactions with triazole antifungal drugs that are important for drug design and understanding drug resistance.

Original languageEnglish (US)
Pages (from-to)3865-3870
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number10
DOIs
StatePublished - Mar 11 2014

ASJC Scopus subject areas

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    Monk, B. C., Tomasiak, T. M., Keniya, M. V., Huschmann, F. U., Tyndall, J. D. A., O'Connell, J. D., Cannon, R. D., McDonald, J. G., Rodriguez, A., Finer-Moore, J. S., & Stroud, R. M. (2014). Architecture of a single membrane spanning cytochrome P450 suggests constraints that orient the catalytic domain relative to a bilayer. Proceedings of the National Academy of Sciences of the United States of America, 111(10), 3865-3870. https://doi.org/10.1073/pnas.1324245111