DOI: 10.1073/pnas.2133986100. An open conformation of mammalian cytochrome P450 2B4 at 1.6-Å resolution

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

10.1073/pnas.2133986100

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

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.

Bibliography

Scott, E. E., He, Y. A., Wester, M. R., White, M. A., Chin, C. C., Halpert, J. R., Johnson, E. F., & Stout, C. D. (2003). An open conformation of mammalian cytochrome P450 2B4 at 1.6-Ã resolution. Proceedings of the National Academy of Sciences, 100(23), 13196â13201.

Authors 8

Emily E. Scott (first)
You Ai He (additional)
Michael R. Wester (additional)
Mark A. White (additional)
Christopher C. Chin (additional)
James R. Halpert (additional)
Eric F. Johnson (additional)
C. David Stout (additional)

References 29 Referenced 303

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10.1111/j.1749-6632.1973.tb47613.x
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Coon, M. J., Vaz, A. D. N., McGinnity, D. F. & Peng, H.-M. (1998) Drug Metab. Dispos. 26, 1190-1193.9860926 / Drug Metab. Dispos. (1998)
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Brunger, A. T., Adams, P. D., Clore, G. M., Delano, W. L., Gros, P., Gross-Kunsleve, R. W., Jiang, J. S., Kuszewski, J., Nilges, N., Pannu, N. S., et al. (1998) Acta Crystallogr. D 64, 905-921. / Acta Crystallogr. D (1998)
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10.1016/S0076-6879(97)77028-9

Dates

Type	When
Created	21 years, 9 months ago (Nov. 16, 2003, 3:42 p.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 7:43 a.m.)
Indexed	1 month, 1 week ago (July 28, 2025, 2:30 a.m.)
Issued	21 years, 10 months ago (Oct. 16, 2003)
Published	21 years, 10 months ago (Oct. 16, 2003)
Published Online	21 years, 10 months ago (Oct. 16, 2003)
Published Print	21 years, 9 months ago (Nov. 11, 2003)

Funders 0

None

BibTeX

@article{Scott_2003, title={An open conformation of mammalian cytochrome P450 2B4 at 1.6-Å resolution}, volume={100}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.2133986100}, DOI={10.1073/pnas.2133986100}, number={23}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Scott, Emily E. and He, You Ai and Wester, Michael R. and White, Mark A. and Chin, Christopher C. and Halpert, James R. and Johnson, Eric F. and Stout, C. David}, year={2003}, month=oct, pages={13196–13201} }

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