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Structures of Cytochrome P450 Enzymes

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Cytochrome P450

Abstract

The protein database has >  450 entries with P450 in the title and of these there are approximately 54 unique structures. Although this sample of unique structures is small relative to the large number of P450s in Nature, it now is clear that the overall P450-fold is highly conserved and restricted to P450s and a small handful of other heme–thiolate enzymes. These crystal structures exhibit adaptations that underlie interactions with specific protein partners and in eukaryotes contribute to membrane binding. A handful of structures now have been solved in both the substrate-free open and substrate-bound closed states, and, while the details may differ among P450s, the open/close motion is very similar and involves the same elements of secondary structure. While the open form is more flexible, and thus may sample a number of isoenergetic conformations, highly specific P450s have only one unique substrate-bound conformation. In sharp contrast, for drug-metabolizing P450s, those regions most important for the open/close equilibrium also can adapt to substrates of different sizes, shapes, and chemical properties and is a unique design feature of these nonspecific P450s. Critical to understanding precisely how and which regions are most adaptable in drug-metabolizing P450s are the increasing number of ligand-bound structures.

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Acknowledgments

TLP would like to thank members of the UCI P450 group, Dipanwita Batabyal, Huiying Li, Irina Sevrioukova, and Sarvind Tripathi, as well as NIH grant GM32688. EFJ would like to thank his colleagues at TSRI, Mei Hsu, Ying Fan, and C. David Stout, as well as the support of NIH Grant GM031001.

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Authors and Affiliations

  1. Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, 2206 Natural Sciences 1, Mail Code 3900, University of California, 92697-3900, Irvine, CA, USA

    Prof. Thomas L. Poulos

  2. Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550N, Torrey Pines Rd., 92037-1000, La Jolla, CA, USA

    Eric F. Johnson

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Correspondence to Thomas L. Poulos .

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  1. University of California, San Francisco, San Francisco, California, USA

    Paul R. Ortiz de Montellano

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Poulos, T., Johnson, E. (2015). Structures of Cytochrome P450 Enzymes. In: Ortiz de Montellano, P. (eds) Cytochrome P450. Springer, Cham. https://doi.org/10.1007/978-3-319-12108-6_1

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