Structural diversity of eukaryotic membrane cytochrome P450s

Journal of Biological Chemistry

Volumn 288, Issue 24, 2013, Pages 17082-17092

  Johnson, Eric F ^a   Stout, C David ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DRUG CLEARANCE; MITOCHONDRIAL CYTOCHROME; STRUCTURAL DIVERSITY; STRUCTURE-FUNCTION RELATION; SUBSTRATE BINDING; X RAY CRYSTAL STRUCTURES;

BIOCHEMISTRY;

BIOLOGY;

CYTOCHROME P450; CYTOCHROME P450 1A1; CYTOCHROME P450 1A2; CYTOCHROME P450 1B1; CYTOCHROME P450 2A6; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 2E1; CYTOCHROME P450 3A4; ISOMERASE; MITOCHONDRIAL ENZYME;

CRYSTAL STRUCTURE; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME CONFORMATION; ENZYME STRUCTURE; ENZYME SUBSTRATE COMPLEX; MEMBRANE BINDING; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; SHORT SURVEY; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

CARCINOGENESIS; CYTOCHROME P450; DRUG DEVELOPMENT; DRUG METABOLISM; PROTEIN STRUCTURE; STEROIDOGENESIS;

ANIMALS; CARCINOGENS; CATALYTIC DOMAIN; CELL MEMBRANE; CYTOCHROME P-450 ENZYME SYSTEM; HUMANS; MEMBRANE PROTEINS; METABOLIC DETOXICATION, DRUG; MITOCHONDRIA; MODELS, MOLECULAR; PROTEIN STRUCTURE, SECONDARY; PROTEIN TRANSPORT;

EUKARYOTA;

EID: 84879053714     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.R113.452805     Document Type: Short Survey

References (99)

1. Nelson, D. R., Zeldin, D. C., Hoffman, S. M., Maltais, L. J., Wain, H. M., and Nebert, D. W. (2004) Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 14, 1-18 (Pubitemid 38183957)
2. Thomas, J. H. (2007) Rapid birth-death evolution specific to xenobiotic cytochrome P450 genes in vertebrates. PLoS Genet. 3, e67
3. Williams, P. A., Cosme, J., Sridhar, V., Johnson, E. F., and McRee, D. E. (2000) The crystallographic structure of a mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity. Mol. Cell 5, 121-131 (Pubitemid 30105441)
4. Poulos, T. L., Finzel, B. C., Gunsalus, I. C., Wagner, G. C., and Kraut, J. (1985) The 2.6-Å crystal structure of the Pseudomonas putida cytochrome P-450. J. Biol. Chem. 260, 16122-16130 (Pubitemid 16176995)
5. Poulos, T. L., and Johnson, E. F. (2005) Structures of cytochrome P450 enzymes. In Cytochrome P450: Structure, Mechanism, and Biochemistry (Ortiz de Montellano, P. R., ed) 3rd Ed., pp. 87-114, Kluwer Academic/Plenum Publishers, New York
6. Sirim, D., Widmann, M., Wagner, F., and Pleiss, J. (2010) Prediction and analysis of the modular structure of cytochrome P450 monooxygenases. BMC Struct. Biol. 10, 34
7. Rittle, J., and Green, M. T. (2010) Cytochrome P450 compound I: capture, characterization, and C-H bond activation kinetics. Science 330, 933-937
8. 5 and cytochrome P450 reductase. J. Biol. Chem. 273, 17036-17049
9. Sevrioukova, I. F., Li, H., Zhang, H., Peterson, J. A., and Poulos, T. L. (1999) Structure of a cytochrome P450-redox partner electron-transfer complex. Proc. Natl. Acad. Sci. U.S.A. 96, 1863-1868 (Pubitemid 29117833)
10. Strushkevich, N., MacKenzie, F., Cherkesova, T., Grabovec, I., Usanov, S., and Park, H. W. (2011) Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Proc. Natl. Acad. Sci. U.S.A. 108, 10139-10143
11. Zhang, W., Pochapsky, S. S., Pochapsky, T. C., and Jain, N. U. (2008) Solution NMR structure of putidaredoxin-cytochrome P450cam complex via a combined residual dipolar coupling-spin labeling approach suggests a role for Trp106 of putidaredoxin in complex formation. J. Mol. Biol. 384, 349-363
12. Ewen, K. M., Kleser, M., and Bernhardt, R. (2011) Adrenodoxin: the archetype of vertebrate-type [2Fe-2S] cluster ferredoxins. Biochim. Biophys. Acta 1814, 111-125
13. Wang, M., Roberts, D. L., Paschke, R., Shea, T. M., Masters, B. S. S., and Kim, J. J. P. (1997) Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes. Proc. Natl. Acad. Sci. U.S.A. 94, 8411-8416 (Pubitemid 27335052)
14. Xia, C., Hamdane, D., Shen, A. L., Choi, V., Kasper, C. B., Pearl, N. M., Zhang, H., Im, S. C., Waskell, L., and Kim, J. J. (2011) Conformational changes of NADPH-cytochrome P450 oxidoreductase are essential for catalysis and cofactor binding. J. Biol. Chem. 286, 16246-16260
15. Hamdane, D., Xia, C., Im, S. C., Zhang, H., Kim, J. J., and Waskell, L. (2009) Structure and function of an NADPH-cytochrome P450 oxidoreductase in an open conformation capable of reducing cytochrome P450. J. Biol. Chem. 284, 11374-11384
16. Im, S. C., and Waskell, L. (2011) The interaction of microsomal cytohrome P450 2B4 with its redox partners, cytochrome P450 reductase and cytochrome b5. Arch. Biochem. Biophys. 507, 144-153
17. Ravichandran, K. G., Boddupalli, S. S., Hasermann, C. A., Peterson, J. A., and Deisenhofer, J. (1993) Crystal structure of hemoprotein domain of P450BM-3, a prototype for microsomal P450s. Science 261, 731-736 (Pubitemid 23278388)
18. Li, H., and Poulos, T. L. (1997) The structure of the cytochrome P450BM-3 haem domain complexed with the fatty acid substrate, palmitoleic acid. Nat. Struct. Biol. 4, 140-146 (Pubitemid 27066389)
19. Cojocaru, V., Winn, P. J., and Wade, R. C. (2007) The ins and outs of cytochrome P450s. Biochim. Biophys. Acta 1770, 390-401 (Pubitemid 46136742)
20. Black, S. D. (1992) Membrane topology of the mammalian P450 cytochromes. FASEB J. 6, 680-685
21. Ghosh, D., Griswold, J., Erman, M., and Pangborn, W. (2010) X-ray structure of human aromatase reveals an androgen-specific active site. J. Steroid Biochem. Mol. Biol. 118, 197-202
22. Cosme, J., and Johnson, E. F. (2000) Engineering microsomal cytochrome P450 2C5 to be a soluble, monomeric enzyme. Mutations that alter aggregation, phospholipid dependence of catalysis, and membrane binding. J. Biol. Chem. 275, 2545-2553 (Pubitemid 30082019)
23. Von Wachenfeldt, C., and Johnson, E. F. (1995) Structures of eukaryotic cytochrome P450 enzymes. In Cytochrome P450: Structure, Mechanism, and Biochemistry (Ortiz de Montellano, P. R., ed) 2nd Ed., pp. 183-223, Plenum Press, New York
24. Ozalp, C., Szczesna-Skorupa, E., and Kemper, B. (2006) Identification of membrane-contacting loops of the catalytic domain of cytochrome P450 2C2 by tryptophan fluorescence scanning. Biochemistry 45, 4629-4637
25. Mast, N., Liao, W. L., Pikuleva, I. A., and Turko, I. V. (2009) Combined use of mass spectrometry and heterologous expression for identification of membrane-interacting peptides in cytochrome P450 46A1 and NADPH-cytochrome P450 oxidoreductase. Arch. Biochem. Biophys. 483, 81-89
26. Denisov, I. G., Shih, A. Y., and Sligar, S. G. (2012) Structural differences between soluble and membrane bound cytochrome P450s. J. Inorg. Biochem. 108, 150-158
27. DuBois, R. N., Simpson, E. R., Tuckey, J., Lambeth, J. D., and Waterman, M. R. (1981) Evidence for a higher molecular weight precursor of cholesterol side chain cleavage cytochrome P-450 and induction of mitochondrial and cytosolic proteins by corticotropin in adult bovine adrenal cells. Proc. Natl. Acad. Sci. U.S.A. 78, 1028-1032 (Pubitemid 11100763)
28. Nabi, N., Kominami, S., Takemori, S., and Omura, T. (1980) In vitro synthesis of mitochondrial cytochromes P-450(scc) and P-450 (11-β) and microsomal cytochrome P-450(C-21) by both free and bound polysomes isolated from bovine adrenal cortex. Biochem. Biophys. Res. Commun. 97, 687-693
29. Headlam, M. J., Wilce, M. C., and Tuckey, R. C. (2003) The F-G loop region of cytochrome P450scc (CYP11A1) interacts with the phospholipid membrane. Biochim. Biophys. Acta 1617, 96-108 (Pubitemid 37456717)
30. Annalora, A. J., Goodin, D. B., Hong, W. X., Zhang, Q., Johnson, E. F., and Stout, C. D. (2010) The crystal structure of CYP24A1, a mitochondrial cytochrome P450 involved in vitamin D metabolism. J. Mol. Biol. 396, 441-451
31. Berka, K., Hendrychová, T., Anzenbacher, P., and Otyepka, M. (2011) Membrane position of ibuprofen agrees with suggested access path entrance to cytochrome P450 2C9 active site. J. Phys. Chem. A 115, 11248-11255
32. Cojocaru, V., Balali-Mood, K., Sansom, M. S., and Wade, R. C. (2011) Structure and dynamics of the membrane-bound cytochrome P450 2C9. PLoS Comput. Biol. 7, e1002152
33. Mast, N., Annalora, A. J., Lodowski, D. T., Palczewski, K., Stout, C. D., and Pikuleva, I. A. (2011) Structural basis for three-step sequential catalysis by the cholesterol side chain cleavage enzyme CYP11A1. J. Biol. Chem. 286, 5607-5613
34. Mast, N., White, M. A., Bjorkhem, I., Johnson, E. F., Stout, C. D., and Pikuleva, I. A. (2008) Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc. Natl. Acad. Sci. U.S.A. 105, 9546-9551 (Pubitemid 352031338)
35. Mast, N., Linger, M., Clark, M., Wiseman, J., Stout, C. D., and Pikuleva, I. A. (2012) In silico and intuitive predictions of CYP46A1 inhibition by marketed drugs with subsequent enzyme crystallization in complex withfluvoxamine. Mol. Pharmacol. 82, 824-834
36. Mast, N., Charvet, C., Pikuleva, I. A., and Stout, C. D. (2010) Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain. J. Biol. Chem. 285, 31783-31795
37. 3. J. Mol. Biol. 380, 95-106
38. Akhtar, M., Wright, J. N., and Lee-Robichaud, P. (2011)Areview of mechanistic studies on aromatase (CYP19) and 17α-hydroxylase-17,20-lyase (CYP17). J. Steroid Biochem. Mol. Biol. 125, 2-12
39. Ghosh, D., Lo, J., Morton, D., Valette, D., Xi, J., Griswold, J., Hubbell, S., Egbuta, C., Jiang, W., An, J., and Davies, H. M. (2012) Novel aromatase inhibitors by structure-guided design. J. Med. Chem. 55, 8464-8476
40. DeVore, N. M., and Scott, E. E. (2012) Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature 482, 116-119
41. Zhao, B., Lei, L., Kagawa, N., Sundaramoorthy, M., Banerjee, S., Nagy, L. D., Guengerich, F. P., and Waterman, M. R. (2012) Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants. J. Biol. Chem. 287, 10613-10622
42. Strushkevich, N., Gilep, A. A., Shen, L., Arrowsmith, C. H., Edwards, A. M., Usanov, S. A., and Park, H. W. (2013) Structural insights into aldosterone synthase substrate specificity and targeted inhibition. Mol. Endocrinol. 27, 315-324
43. Strushkevich, N., Usanov, S. A., and Park, H. W. (2010) Structural basis of human CYP51 inhibition by antifungal azoles. J. Mol. Biol. 397, 1067-1078
44. Lepesheva, G. I., Park, H. W., Hargrove, T. Y., Vanhollebeke, B., Wawrzak, Z., Harp, J. M., Sundaramoorthy, M., Nes, W. D., Pays, E., Chaudhuri, M., Villalta, F., and Waterman, M. R. (2010) Crystal structures of Trypanosoma brucei sterol 14α-demethylase and implications for selective treatment of human infections. J. Biol. Chem. 285, 1773-1780
45. Hargrove, T. Y., Wawrzak, Z., Liu, J., Waterman, M. R., Nes, W. D., and Lepesheva, G. I. (2012) Structural complex of sterol 14α-demethylase (CYP51) with 14α-methylenecyclopropyl-Δ7-24,25-dihydrolanosterol. J. Lipid Res. 53, 311-320
46. Lepesheva, G. I., Hargrove, T. Y., Anderson, S., Kleshchenko, Y., Furtak, V., Wawrzak, Z., Villalta, F., and Waterman, M. R. (2010) Structural insights into inhibition of sterol 14α-demethylase in the human pathogen Trypanosoma cruzi. J. Biol. Chem. 285, 25582-25590
47. Chiang, C. W., Yeh, H. C., Wang, L. H., and Chan, N. L. (2006) Crystal structure of the human prostacyclin synthase. J. Mol. Biol. 364, 266-274
48. Li, Y. C., Chiang, C. W., Yeh, H. C., Hsu, P. Y., Whitby, F. G., Wang, L. H., and Chan, N. L. (2008) Structures of prostacyclin synthase and its complexes with substrate-analog and inhibitor reveal a ligand-specific heme conformation change. J. Biol. Chem. 283, 2917-2926
49. 2 biosynthesis. J. Biol. Chem. 264, 141-150
50. Lee, D. S., Nioche, P., Hamberg, M., and Raman, C. S. (2008) Structural insights into the evolutionary paths of oxylipin biosynthetic enzymes. Nature 455, 363-368
51. Rendic, S., and Guengerich, F. P. (2012) Contributions of human enzymes in carcinogen metabolism. Chem. Res. Toxicol. 25, 1316-1383
52. Sansen, S., Yano, J. K., Reynald, R. L., Schoch, G. A., Griffin, K. J., Stout, C. D., and Johnson, E. F. (2007) Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2. J. Biol. Chem. 282, 14348-14355 (Pubitemid 47100434)
53. Wang, A., Savas, U., Stout, C. D., and Johnson, E. F. (2011) Structural characterization of the complex between α-naphthoflavone and human cytochrome P450 1B1. J. Biol. Chem. 286, 5736-5743
54. Gotoh, O. (1992) Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. J. Biol. Chem. 267, 83-90
55. Yano, J. K., Hsu, M. H., Griffin, K. J., Stout, C. D., and Johnson, E. F. (2005) Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen. Nat. Struct. Mol. Biol. 12, 822-823 (Pubitemid 43086258)
56. DeVore, N. M., and Scott, E. E. (2012) Nicotine and 4-(methylnitro- samino)-1-(3-pyridyl)-1-butanone binding and access channel in human cytochrome P450 2A6 and 2A13 enzymes. J. Biol. Chem. 287, 26576-26585
57. Yano, J. K., Denton, T. T., Cerny, M. A., Zhang, X., Johnson, E. F., and Cashman, J. R. (2006) Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization. J. Med. Chem. 49, 6987-7001 (Pubitemid 44885987)
58. Smith, B. D., Sanders, J. L., Porubsky, P. R., Lushington, G. H., Stout, C. D., and Scott, E. E. (2007) Structure of the human lung cytochrome P450 2A13. J. Biol. Chem. 282, 17306-17313 (Pubitemid 47093207)
59. Porubsky, P. R., Meneely, K. M., and Scott, E. E. (2008) Structures of human cytochrome P450 2E1. Insights into the binding of inhibitors and both small molecular weight and fatty acid substrates. J. Biol. Chem. 283, 33698-33707
60. Porubsky, P. R., Battaile, K. P., and Scott, E. E. (2010) Human cytochrome P450 2E1 structures with fatty acid analogs reveal a previously unobserved binding mode. J. Biol. Chem. 285, 22282-22290
61. DeVore, N. M., Meneely, K. M., Bart, A. G., Stephens, E. S., Battaile, K. P., and Scott, E. E. (2012) Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine. FEBS J. 279, 1621-1631
62. Cruciani, G., Carosati, E., De Boeck, B., Ethirajulu, K., Mackie, C., Howe, T., and Vianello, R. (2005) MetaSite: understanding metabolism in human cytochromes from the perspective of the chemist. J. Med. Chem. 48, 6970-6979 (Pubitemid 41533118)
63. de Groot, M. J. (2006) Designing better drugs: predicting cytochrome P450 metabolism. Drug Discov. Today 11, 601-606
64. Sun, H., and Scott, D. O. (2010) Structure-based drug metabolism predictions for drug design. Chem. Biol. Drug Des. 75, 3-17
65. Kirchmair, J., Williamson, M. J., Tyzack, J. D., Tan, L., Bond, P. J., Bender, A., and Glen, R. C. (2012) Computational prediction of metabolism: sites, products, SAR, P450 enzyme dynamics, and mechanisms. J. Chem. Inf. Model. 52, 617-648
66. Zanger, U. M., Turpeinen, M., Klein, K., and Schwab, M. (2008) Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal. Bioanal. Chem. 392, 1093-1108
67. Yano, J. K., Wester, M. R., Schoch, G. A., Griffin, K. J., Stout, C. D., and Johnson, E. F. (2004) The structure of human microsomal cytochrome P450 3A4 determined by x-ray crystallography to 2.05-Å resolution. J. Biol. Chem. 279, 38091-38094 (Pubitemid 39295952)
68. Williams, P. A., Cosme, J., Vinkovic, D. M., Ward, A., Angove, H. C., Day, P. J., Vonrhein, C., Tickle, I. J., and Jhoti, H. (2004) Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science 305, 683-686 (Pubitemid 39006760)
69. Ekroos, M., and Sjögren, T. (2006) Structural basis for ligand promiscuity in cytochrome P450 3A4. Proc. Natl. Acad. Sci. U.S.A. 103, 13682-13687 (Pubitemid 44413967)
70. Sevrioukova, I. F., and Poulos, T. L. (2010) Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir. Proc. Natl. Acad. Sci. U.S.A. 107, 18422-18427
71. Sevrioukova, I. F., and Poulos, T. L. (2012) Interaction of human cytochrome P4503A4 with ritonavir analogs. Arch. Biochem. Biophys. 520, 108-116
72. Sevrioukova, I. F., and Poulos, T. L. (2012) Structural and mechanistic insights into the interaction of cytochrome P4503A4 with bromoergocryptine, a type I ligand. J. Biol. Chem. 287, 3510-3517
73. Isin, E. M., and Guengerich, F. P. (2008) Substrate binding to cytochromes P450. Anal Bioanal. Chem. 392, 1019-1030
74. Denisov, I. G., and Sligar, S. G. (2012) A novel type of allosteric regulation: functional cooperativity in monomeric proteins. Arch. Biochem. Biophys. 519, 91-102
75. Roberts, A. G., Yang, J., Halpert, J. R., Nelson, S. D., Thummel, K. T., and Atkins, W. M. (2011) The structural basis for homotropic and heterotropic cooperativity of midazolam metabolism by human cytochrome P450 3A4. Biochemistry 50, 10804-10818
76. Davydov, D. R., Rumfeldt, J. A., Sineva, E. V., Fernando, H., Davydova, N. Y., and Halpert, J. R. (2012) Peripheral ligand-binding site in cytochrome P450 3A4 located with fluorescence resonance energy transfer (FRET). J. Biol. Chem. 287, 6797-6809
77. Schoch, G. A., Yano, J. K., Sansen, S., Dansette, P. M., Stout, C. D., and Johnson, E. F. (2008) Determinants of cytochrome P450 2C8 substrate binding. Structures of complexes with montelukast, troglitazone, felodipine, and 9-cis-retinoic acid. J. Biol. Chem. 283, 17227-17237
78. Schoch, G. A., Yano, J. K., Wester, M. R., Griffin, K. J., Stout, C. D., and Johnson, E. F. (2004) Structure of human microsomal cytochrome P450 2C8. Evidence for a peripheral fatty acid binding site. J. Biol. Chem. 279, 9497-9503 (Pubitemid 38296017)
79. Reynald, R. L., Sansen, S., Stout, C. D., and Johnson, E. F. (2012) Structural characterization of human cytochrome P450 2C19. Active site differences between P450s 2C8, 2C9, and 2C19. J. Biol. Chem. 287, 44581-44591
80. Wester, M. R., Johnson, E. F., Marques-Soares, C., Dansette, P. M., Mansuy, D., and Stout, C. D. (2003) The structure of a substrate complex of mammalian cytochrome P450 2C5 at 2.3 Å resolution: evidence for multiple substrate binding modes. Biochemistry 42, 6370-6379 (Pubitemid 36665811)
81. Wester, M. R., Johnson, E. F., Marques-Soares, C., Dijols, S., Dansette, P. M., Mansuy, D., and Stout, C. D. (2003) The structure of mammalian cytochrome P450 2C5 complexed with diclofenac at 2.1 Å resolution: evidence for an induced fit model of substrate binding. Biochemistry 42, 9335-9345 (Pubitemid 36959241)
82. Wester, M. R., Yano, J. K., Schoch, G. A., Yang, C., Griffin, K. J., Stout, C. D., and Johnson, E. F. (2004) The structure of human microsomal cytochrome P450 2C9 complexed with flurbiprofen at 2.0 Å resolution. J. Biol. Chem. 279, 35630-35637 (Pubitemid 39100565)
83. Williams, P. A., Cosme, J., Ward, A., Angove, H. C., Matak Vinković, D., and Jhoti, H. (2003) Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature 424, 464-468 (Pubitemid 36917499)
84. Rowland, P., Blaney, F. E., Smyth, M. G., Jones, J. J., Leydon, V. R., Oxbrow, A. K., Lewis, C. J., Tennant, M. G., Modi, S., Eggleston, D. S., Chenery, R. J., and Bridges, A. M. (2006) Crystal structure of human cytochrome P450 2D6. J. Biol. Chem. 281, 7614-7622 (Pubitemid 43847532)
85. Wang, A., Savas, U., Hsu, M. H., Stout, C. D., and Johnson, E. F. (2012) Crystal structure of human cytochrome P450 2D6 with prinomastat bound. J. Biol. Chem. 287, 10834-10843
86. Wang, B., Yang, L. P., Zhang, X. Z., Huang, S. Q., Bartlam, M., and Zhou, S. F. (2009) New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme. Drug Metab. Rev. 41, 573-643
87. Scott, E. E., He, Y. A., Wester, M. R., White, M. A., Chin, C. C., Halpert, J. R., Johnson, E. F., and Stout, C. D. (2003) An open conformation of mammalian cytochrome P450 2B4 at 1.6-Å resolution. Proc. Natl. Acad. Sci. U.S.A. 100, 13196-13201 (Pubitemid 37444718)
88. Scott, E. E., White, M. A., He, Y. A., Johnson, E. F., Stout, C. D., and Halpert, J. R. (2004) Structure of mammalian cytochrome P450 2B4 complexed with 4-(4-chlorophenyl)imidazole at 1.9 Å resolution. Insight into the range of P450 conformations and coordination of redox partner binding. J. Biol. Chem. 279, 27294-27301 (Pubitemid 38812569)
89. Zhao, Y., Sun, L., Muralidhara, B. K., Kumar, S., White, M. A., Stout, C. D., and Halpert, J. R. (2007) Structural and thermodynamic consequences of 1-(4-chlorophenyl)imidazole binding to cytochrome P450 2B4. Biochemistry 46, 11559-11567 (Pubitemid 47585501)
90. Gay, S. C., Shah, M. B., Talakad, J. C., Maekawa, K., Roberts, A. G., Wilderman, P. R., Sun, L., Yang, J. Y., Huelga, S. C., Hong, W. X., Zhang, Q., Stout, C. D., and Halpert, J. R. (2010) Crystal structure of a cytochrome P450 2B6 genetic variant in complex with the inhibitor 4-(4-chlorophenyl) imidazole at 2.0-Å resolution. Mol. Pharmacol. 77, 529-538
91. Gay, S. C., Roberts, A. G., Maekawa, K., Talakad, J. C., Hong, W. X., Zhang, Q., Stout, C. D., and Halpert, J. R. (2010) Structures of cytochrome P450 2B4 complexed with the antiplatelet drugs ticlopidine and clopidogrel. Biochemistry 49, 8709-8720
92. Wilderman, P. R., Shah, M. B., Liu, T., Li, S., Hsu, S., Roberts, A. G., Goodlett, D. R., Zhang, Q., Woods, V. L., Jr., Stout, C. D., and Halpert, J. R. (2010) Plasticity of cytochrome P450 2B4 as investigated by hydrogendeuterium exchange mass spectrometry and x-ray crystallography. J. Biol. Chem. 285, 38602-38611
93. Shah, M. B., Pascual, J., Zhang, Q., Stout, C. D., and Halpert, J. R. (2011) 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. Mol. Pharmacol. 80, 1047-1055
94. Gay, S. C., Sun, L., Maekawa, K., Halpert, J. R., and Stout, C. D. (2009) Crystal structures of cytochrome P450 2B4 in complex with the inhibitor 1-biphenyl-4-methyl-1H-imidazole: ligand-induced structural response through α-helical repositioning. Biochemistry 48, 4762-4771
95. Zhao, Y., White, M. A., Muralidhara, B. K., Sun, L., Halpert, J. R., and Stout, C. D. (2006) Structure of microsomal cytochrome P450 2B4 complexed with the antifungal drug bifonazole. Insight into P450 conformational plasticity and membrane interaction. J. Biol. Chem. 281, 5973-5981 (Pubitemid 43847698)
96. Halpert, J. R. (2011) The 2010 Bernard B. Brodie Award Lecture. Structure and function of cytochromes P450 2B: from mechanism-based inactivators to x-ray crystal structures and back. Drug Metab. Dispos. 39, 1113-1121
97. Shah, M. B., Wilderman, P. R., Pascual, J., Zhang, Q., Stout, C. D., and Halpert, J. R. (2012) Conformational adaptation of human cytochrome P450 2B6 and rabbit cytochrome P450 2B4 revealed upon binding multiple amlodipine molecules. Biochemistry 18, 7225-7238
98. Zhang, H., Gay, S. C., Shah, M., Foroozesh, M., Liu, J., Osawa, Y., Zhang, Q., Stout, C. D., Halpert, J. R., and Hollenberg, P. F. (2013) Potent mech-anism- based inactivation of cytochrome P450 2B4 by 9-ethynylphenanthrene: implications for allosteric modulation of cytochrome P450 catalysis. Biochemistry 52, 355-364
99. Gay, S. C., Zhang, H., Wilderman, P. R., Roberts, A. G., Liu, T., Li, S., Lin, H. L., Zhang, Q., Woods, V. L., Jr., Stout, C. D., Hollenberg, P. F., and Halpert, J. R. (2011) Structural analysis of mammalian cytochrome P450 2B4 covalently bound to the mechanism-based inactivator tert-butylphenylacetylene: insight into partial enzymatic activity. Biochemistry 50, 4903-4911