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Probing the open state of cytochrome P450cam with ruthenium-linker substrates

Dunn, Alexander R. and Dmochowski, Ivan J. and Bilwes, Alexandrine M. and Gray, Harry B. and Crane, Brian R. (2001) Probing the open state of cytochrome P450cam with ruthenium-linker substrates. Proceedings of the National Academy of Sciences of the United States of America, 98 (22). pp. 12420-12425. ISSN 0027-8424. PMCID PMC60069. http://resolver.caltech.edu/CaltechAUTHORS:DUNpnas01

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Abstract

Cytochromes P450 play key roles in drug metabolism and disease by oxidizing a wide variety of natural and xenobiotic compounds. High-resolution crystal structures of P450cam bound to ruthenium sensitizer-linked substrates reveal an open conformation of the enzyme that allows substrates to access the active center via a 22-Angstrom deep channel. Interactions of alkyl and fluorinated biphenyl linkers with the channel demonstrate the importance of exploiting protein dynamics for specific inhibitor design. Large changes in peripheral enzyme structure (F and G helices) couple to conformational changes in active center residues (I helix) implicated in proton pumping and dioxygen activation. Common conformational states among P450cam and homologous enzymes indicate that static and dynamic variability in the F/G helix region allows the 54 human P450s to oxidize thousands of substrates.


Item Type:Article
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC60069/PubMed CentralArticle
Additional Information:© 2001 by the National Academy of Sciences. Edited by Stephen J. Benkovic, Pennsylvania State University, University Park, PA, and approved August 15, 2001 (received for review June 12, 2001). Published online before print October 16, 2001, 10.1073/pnas.221297998 We thank Stanford Synchrotron Research Laboratory for access to data collection facilities and the staff of beamlines 9-1 and 9-2 for their assistance with data collection. This work was supported by the Fannie and John Hertz Foundation (to A.R.D.), the Helen Hay Whitney Foundation (to B.R.C.), the National Institutes of Health predoctoral program (to I.J.D.), the National Science Foundation, and the National Institutes of Health. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Funders:
Funding AgencyGrant Number
Fannie and John Hertz FoundationUNSPECIFIED
Helen Hay Whitney FoundationUNSPECIFIED
NIH Predoctoral FellowshipUNSPECIFIED
NSFUNSPECIFIED
Subject Keywords:nitric-oxide reductase, crystal-structure, conformational dynamics, active-site, heme domain, P450BM-3, binding, water, hexafluorobenzene, crystallography
Issue or Number:22
PubMed Central ID:PMC60069
Record Number:CaltechAUTHORS:DUNpnas01
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:DUNpnas01
Alternative URL:http://dx.doi.org/10.1073/pnas.221297998
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:986
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:22 Nov 2005
Last Modified:26 May 2017 21:50

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