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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.

Shah MB, Pascual J, Zhang Q, Stout CD, Halpert JR
Mol Pharmacol 80 1047-55 (2011)
Cited: 32 times
EuropePMC logo PMID: 21875942

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.

Reviews - 3qoa mentioned but not cited (1)

  1. Ligand Access Channels in Cytochrome P450 Enzymes: A Review. Urban P, Lautier T, Pompon D, Truan G. Int J Mol Sci 19 E1617 (2018)

Articles - 3qoa mentioned but not cited (6)

  1. 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. Shah MB, Pascual J, Zhang Q, Stout CD, Halpert JR. Mol Pharmacol 80 1047-1055 (2011)
  2. Lecture Structure and function of cytochromes P450 2B: from mechanism-based inactivators to X-ray crystal structures and back. Halpert JR. Drug Metab Dispos 39 1113-1121 (2011)
  3. Evaluation of influence of single nucleotide polymorphisms in cytochrome P450 2B6 on substrate recognition using computational docking and molecular dynamics simulation. Kobayashi K, Takahashi O, Hiratsuka M, Yamaotsu N, Hirono S, Watanabe Y, Oda A. PLoS One 9 e96789 (2014)
  4. Structural and biophysical characterization of human cytochromes P450 2B6 and 2A6 bound to volatile hydrocarbons: analysis and comparison. Shah MB, Wilderman PR, Liu J, Jang HH, Zhang Q, Stout CD, Halpert JR. Mol Pharmacol 87 649-659 (2015)
  5. Mechanisms of interaction between persistent organic pollutants (POPs) and CYP2B6: An in silico approach. Maldonado-Rojas W, Rivera-Julio K, Olivero-Verbel J, Aga DS. Chemosphere 159 113-125 (2016)
  6. Accumulation properties of polychlorinated biphenyl congeners in Yusho patients and prediction of their cytochrome P450-dependent metabolism by in silico analysis. Hirakawa S, Miyawaki T, Hori T, Kajiwara J, Katsuki S, Hirano M, Yoshinouchi Y, Iwata H, Mitoma C, Furue M. Environ Sci Pollut Res Int 25 16455-16463 (2018)


Reviews citing this publication (9)

  1. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Zanger UM, Schwab M. Pharmacol Ther 138 103-141 (2013)
  2. Structural diversity of eukaryotic membrane cytochrome p450s. Johnson EF, Stout CD. J Biol Chem 288 17082-17090 (2013)
  3. Conformational diversity and ligand tunnels of mammalian cytochrome P450s. Yu X, Cojocaru V, Wade RC. Biotechnol Appl Biochem 60 134-145 (2013)
  4. Modeling of interactions between xenobiotics and cytochrome P450 (CYP) enzymes. Raunio H, Kuusisto M, Juvonen RO, Pentikäinen OT. Front Pharmacol 6 123 (2015)
  5. Substrate selectivity of drug-metabolizing cytochrome P450s predicted from crystal structures and in silico modeling. Dong D, Wu B, Chow D, Hu M. Drug Metab Rev 44 192-208 (2012)
  6. Hepatic cytochromes P450: structural degrons and barcodes, posttranslational modifications and cellular adapters in the ERAD-endgame. Kim SM, Wang Y, Nabavi N, Liu Y, Correia MA. Drug Metab Rev 48 405-433 (2016)
  7. Coumarin-Based Profluorescent and Fluorescent Substrates for Determining Xenobiotic-Metabolizing Enzyme Activities In Vitro. Raunio H, Pentikäinen O, Juvonen RO. Int J Mol Sci 21 E4708 (2020)
  8. Coumarins and P450s, Studies Reported to-Date. Foroozesh M, Sridhar J, Goyal N, Liu J. Molecules 24 E1620 (2019)
  9. Substrate selectivity of drug-metabolizing cytochrome P450s predicted from crystal structures and in silico modeling. Dong D, Wu B. Drug Metab Rev 44 1-17 (2012)

Articles citing this publication (16)

  1. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Zanger UM, Klein K. Front Genet 4 24 (2013)
  2. Steroid-based facial amphiphiles for stabilization and crystallization of membrane proteins. Lee SC, Bennett BC, Hong WX, Fu Y, Baker KA, Marcoux J, Robinson CV, Ward AB, Halpert JR, Stevens RC, Stout CD, Yeager MJ, Zhang Q. Proc Natl Acad Sci U S A 110 E1203-11 (2013)
  3. Conformational adaptation of human cytochrome P450 2B6 and rabbit cytochrome P450 2B4 revealed upon binding multiple amlodipine molecules. Shah MB, Wilderman PR, Pascual J, Zhang Q, Stout CD, Halpert JR. Biochemistry 51 7225-7238 (2012)
  4. Oxidation of methyl and ethyl nitrosamines by cytochrome P450 2E1 and 2B1. Chowdhury G, Calcutt MW, Nagy LD, Guengerich FP. Biochemistry 51 9995-10007 (2012)
  5. Structural and thermodynamic basis of (+)-α-pinene binding to human cytochrome P450 2B6. Wilderman PR, Shah MB, Jang HH, Stout CD, Halpert JR. J Am Chem Soc 135 10433-10440 (2013)
  6. Cytochrome p450 architecture and cysteine nucleophile placement impact raloxifene-mediated mechanism-based inactivation. VandenBrink BM, Davis JA, Pearson JT, Foti RS, Wienkers LC, Rock DA. Mol Pharmacol 82 835-842 (2012)
  7. A structural snapshot of CYP2B4 in complex with paroxetine provides insights into ligand binding and clusters of conformational states. Shah MB, Kufareva I, Pascual J, Zhang Q, Stout CD, Halpert JR. J Pharmacol Exp Ther 346 113-120 (2013)
  8. Structure-Function Analysis of Mammalian CYP2B Enzymes Using 7-Substituted Coumarin Derivatives as Probes: Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism. Shah MB, Liu J, Huo L, Zhang Q, Dearing MD, Wilderman PR, Szklarz GD, Stout CD, Halpert JR. Mol Pharmacol 89 435-445 (2016)
  9. Structure of Cytochrome P450 2C9*2 in Complex with Losartan: Insights into the Effect of Genetic Polymorphism. Parikh SJ, Evans CM, Obi JO, Zhang Q, Maekawa K, Glass KC, Shah MB. Mol Pharmacol 98 529-539 (2020)
  10. Structure-Activity Studies Reveal the Oxazinone Ring Is a Determinant of Cytochrome P450 2B6 Activity Toward Efavirenz. Cox PM, Bumpus NN. ACS Med Chem Lett 5 1156-1161 (2014)
  11. Effect of detergent binding on cytochrome P450 2B4 structure as analyzed by X-ray crystallography and deuterium-exchange mass spectrometry. Shah MB, Jang HH, Wilderman PR, Lee D, Li S, Zhang Q, Stout CD, Halpert JR. Biophys Chem 216 1-8 (2016)
  12. X-ray crystal structure of the cytochrome P450 2B4 active site mutant F297A in complex with clopidogrel: insights into compensatory rearrangements of the binding pocket. Shah MB, Jang HH, Zhang Q, David Stout C, Halpert JR. Arch Biochem Biophys 530 64-72 (2013)
  13. Crystal Structure of CYP2B6 in Complex with an Efavirenz Analog. Shah MB, Zhang Q, Halpert JR. Int J Mol Sci 19 E1025 (2018)
  14. Analysis of Species-Selectivity of Human, Mouse and Rat Cytochrome P450 1A and 2B Subfamily Enzymes using Molecular Modeling, Docking and Dynamics Simulations. Karthikeyan BS, Suvaithenamudhan S, Akbarsha MA, Parthasarathy S. Cell Biochem Biophys 76 91-110 (2018)
  15. Roles of Residues F206 and V367 in Human CYP2B6: Effects of Mutations on Androgen Hydroxylation, Mechanism-Based Inactivation, and Reversible Inhibition. Lin HL, Zhang H, Kenaan C, Hollenberg PF. Drug Metab Dispos 44 1771-1779 (2016)
  16. Use of Phenoxyaniline Analogues To Generate Biochemical Insights into the Interactio n of Polybrominated Diphenyl Ether with CYP2B Enzymes. Chen C, Liu J, Halpert JR, Wilderman PR. Biochemistry 57 817-826 (2018)


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