NDLI: An open conformation of mammalian cytochrome P450 2B4 at 1.6-Å resolution

Content Provider	PubMed Central
Author	Scott, Emily E. He, You Ai Wester, Michael R. White, Mark A. Chin, Christopher C. Halpert, James R. Johnson, Eric F. Stout, C. David
Copyright Year	2003
Abstract	The xenobiotic metabolizing cytochromes P450 (P450s) are among the most versatile biological catalysts known, but knowledge of the structural basis for their broad substrate specificity has been limited. P450 2B4 has been frequently used as an experimental model for biochemical and biophysical studies of these membrane proteins. A 1.6-Å crystal structure of P450 2B4 reveals a large open cleft that extends from the protein surface directly to the heme iron between the α-helical and β-sheet domains without perturbing the overall P450 fold. This cleft is primarily formed by helices B′ to C and F to G. The conformation of these regions is dramatically different from that of the other structurally defined mammalian P450, 2C5/3LVdH, in which the F to G and B′ to C regions encapsulate one side of the active site to produce a closed form of the enzyme. The open conformation of 2B4 is trapped by reversible formation of a homodimer in which the residues between helices F and G of one molecule partially fill the open cleft of a symmetry-related molecule, and an intermolecular coordinate bond occurs between H226 and the heme iron. This dimer is observed both in solution and in the crystal. Differences between the structures of 2C5 and 2B4 suggest that defined regions of xenobiotic metabolizing P450s may adopt a substantial range of energetically accessible conformations without perturbing the overall fold. This conformational flexibility is likely to facilitate substrate access, metabolic versatility, and product egress.
Related Links	http://dx.doi.org/10.1073/pnas.2133986100
Ending Page	13201
Page Count	6
Starting Page	13196
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	23
Volume Number	100
Language	English
Publisher	National Academy of Sciences
Publisher Date	2003-11-11
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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