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Cited by 279

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Structure of Mammalian Cytochrome P450 2B4 Complexed with 4-(4-Chlorophenyl)imidazole at 1.9-Å Resolution

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Scott, Emily E., White, Mark A., He, You Ai, Johnson, Eric F., Stout, C. David, Halpert, James R.·2004·Journal of Biological Chemistry

Abstract

A 1.9-A molecular structure of the microsomal cytochrome P450 2B4 with the specific inhibitor 4-(4-chlorophenyl)imidazole (CPI) in the active site was determined by x-ray crystallography. In contrast to the previous experimentally determined 2B4 structure, this complex adopted a closed conformation similar to that observed for the mammalian 2C enzymes. The differences between the open and closed structures of 2B4 were primarily limited to the lid domain of helices F through G, helices B' and C, the N terminus of helix I, and the beta(4) region. These large-scale conformational changes were generally due to the relocation of conserved structural elements toward each other with remarkably little remodeling at the secondary structure level. For example, the F' and G' helices were maintained with a sharp turn between them but are placed to form the exterior ceiling of the active site in the CPI complex. CPI was closely surrounded by residues from substrate recognition sites 1, 4, 5, and 6 to form a small, isolated hydrophobic cavity. The switch from open to closed conformation dramatically relocated helix C to a more proximal position. As a result, heme binding interactions were altered, and the putative NADPH-cytochrome P450 reductase binding site was reformed. This suggests a structural mechanism whereby ligand-induced conformational changes may coordinate catalytic activity. Comparison of the 2B4/CPI complex with the open 2B4 structure yields insights into the dynamics involved in substrate access, tight inhibitor binding, and coordination of substrate and redox partner binding.

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Metadata

Authors
Scott, E. E., White, M. A., He, Y. A., Johnson, E. F., Stout, C. D., & Halpert, J. R.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2004-06
Volume
279
Issue
26
Pages
27294-27301
ISSN
0021-9258 (ISSN-L)
OpenAlex
W1974543768
Cited by
279
References
34
FWCI
24.87
Type
journal article
Language
en
Open access
hybrid

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CoChat. (2026). Citation check: Structure of Mammalian Cytochrome P450 2B4 Complexed with 4-(4-Chlorophenyl)imidazole at 1.9-Å Resolution. https://app.cochat.ai/papers/10.1074/jbc.m403349200
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Scott, E. E., White, M. A., He, Y. A., Johnson, E. F., Stout, C. D., & Halpert, J. R. (2004). Structure of Mammalian Cytochrome P450 2B4 Complexed with 4-(4-Chlorophenyl)imidazole at 1.9-Å Resolution. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m403349200

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