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Molecular Pharmacology

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Research ArticleArticle

Structures of Cytochrome P450 2B6 Bound to 4-Benzylpyridine and 4-(4-Nitrobenzyl)pyridine: Insight into Inhibitor Binding and Rearrangement of Active Site Side Chains

Manish B. Shah, Jaime Pascual, Qinghai Zhang, C. David Stout and James R. Halpert
Molecular Pharmacology December 2011, 80 (6) 1047-1055; DOI: https://doi.org/10.1124/mol.111.074427
Manish B. Shah
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Jaime Pascual
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Qinghai Zhang
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C. David Stout
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James R. Halpert
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Abstract

The biochemical, biophysical, and structural analysis of the cytochrome P450 2B subfamily of enzymes has provided a wealth of information regarding conformational plasticity and substrate recognition. The recent X-ray crystal structure of the drug-metabolizing P450 2B6 in complex with 4-(4-chlorophenyl)imidazole (4-CPI) yielded the first atomic view of this human enzyme. However, knowledge of the structural basis of P450 2B6 specificity and inhibition has remained limited. In this study, structures of P450 2B6 were determined in complex with the potent inhibitors 4-benzylpyridine (4-BP) and 4-(4-nitrobenzyl)pyridine (4-NBP). Comparison of the present structures with the previous P450 2B6-4-CPI complex showed that reorientation of side chains of the active site residue Phe206 on the F-helix and Phe297 on the I-helix was necessary to accommodate the inhibitors. However, P450 2B6 does not require any major side chain rearrangement to bind 4-NBP compared with 4-BP, and the enzyme provides no hydrogen-bonding partners for the polar nitro group of 4-NBP within the hydrophobic active site. In addition, on the basis of these new structures, substitution of residue 172 with histidine as observed in the single nucleotide polymorphism Q172H and in P450 2B4 may contribute to a hydrogen bonding network connecting the E- and I-helices, thereby stabilizing active site residues on the I-helix. These results provide insight into the role of active site side chains upon inhibitor binding and indicate that the recognition of the benzylpyridines in the closed conformation structure of P450 2B6 is based solely on hydrophobicity, size, and shape.

Footnotes

  • This research was supported by National Institutes of Health National Institute of Environmental Health Sciences [Grant ES003619] (to J.R.H.); and National Institutes of Health National Institute of General Medical Sciences [Grant GM073197] (to Q.Z.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.074427.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    P450 2B6
    an N-terminally truncated and modified and C-terminally His-tagged form of the cytochrome P450 2B6 genetic variant K262R with an internal mutation at position 226
    SNP
    single nucleotide polymorphism
    4-CPI
    4-(4-chlorophenyl)imidazole
    4-BP
    4-benzylpyridine
    4-NBP
    4-(4-nitrobenzyl) pyridine
    7-EFC
    7-ethoxy-(4-trifluoromethyl)coumarin
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
    234-chol
    3R-hydroxy-7R,12R-bis({[2-(tri-methylamino)ethyl]phosphoryl}ethyloxy)cholane
    BME
    2-mercaptoethanol
    PMSF
    phenylmethylsulfonyl fluoride
    DTT
    dithiothreitol
    PDB
    Protein Data Bank
    RMSD
    root mean square deviation
    tBPA
    tert-butylphenylacetylene.

  • Received June 23, 2011.
  • Accepted August 29, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (6)
Molecular Pharmacology
Vol. 80, Issue 6
1 Dec 2011
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Research ArticleArticle

Crystal Structures of Human P450 2B6 Bound to 4-BP and 4-NBP

Manish B. Shah, Jaime Pascual, Qinghai Zhang, C. David Stout and James R. Halpert
Molecular Pharmacology December 1, 2011, 80 (6) 1047-1055; DOI: https://doi.org/10.1124/mol.111.074427

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Research ArticleArticle

Crystal Structures of Human P450 2B6 Bound to 4-BP and 4-NBP

Manish B. Shah, Jaime Pascual, Qinghai Zhang, C. David Stout and James R. Halpert
Molecular Pharmacology December 1, 2011, 80 (6) 1047-1055; DOI: https://doi.org/10.1124/mol.111.074427
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