Probing the open state of cytochrome P450cam with ruthenium-linker substrates
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.
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.Attached Files
Published - DUNpnas01.pdf
Files
Name | Size | Download all |
---|---|---|
md5:c6ed4f45ba749f3017611da9dcf5cf97
|
1.5 MB | Preview Download |
Additional details
- PMCID
- PMC60069
- Eprint ID
- 986
- Resolver ID
- CaltechAUTHORS:DUNpnas01
- Fannie and John Hertz Foundation
- Helen Hay Whitney Foundation
- NIH Predoctoral Fellowship
- NSF
- Created
-
2005-11-22Created from EPrint's datestamp field
- Updated
-
2023-06-01Created from EPrint's last_modified field