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Crystal structures of cytochrome p450 2b4 in complex with the inhibitor 1-biphenyl-4-methyl-1h-imidazole: Ligand-induced structural response through alpha-helical repositioning

Academic Article
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Overview

authors

  • Gay, S. C.
  • Sun, L.
  • Maekawa, K.
  • Halpert, J. R.
  • Stout, C. David

publication date

  • June 2009

journal

  • Biochemistry  Journal

abstract

  • Two different ligand occupancy structures of cytochrome P450 2B4 (CYP2B4) in complex with 1-biphenyl-4-methyl-1H-imidazole (1-PBI) have been determined by X-ray crystallography. 1-PBI belongs to a series of tight binding, imidazole-based CYP2B4 inhibitors. 1-PBI binding to CYP2B4 yields a type II spectrum with a K(s) value of 0.23 microM and inhibits enzyme activity with an IC(50) value of 0.035 microM. Previous CYP2B4 structures have shown a large degree of structural movement in response to ligand size. With two phenyl rings, 1-PBI is larger than 1-(4-chlorophenyl)imidazole (1-CPI) and 4-(4-chlorophenyl)imidazole (4-CPI) but smaller than bifonazole, which is branched and contains three phenyl rings. The CYP2B4-1-PBI complex is a structural intermediate to the closed CPI and the open bifonazole structures. The B/C-loop reorganizes itself to include two short partial helices while closing one side of the active site. The F-G-helix cassette pivots over the I-helix in direct response to the size of the ligand in the active site. A cluster of Phe residues at the fulcrum of this pivot point allows for dramatic repositioning of the cassette with only a relatively small amount of secondary structure rearrangement. Comparisons of ligand-bound CYP2B4 structures reveal trends in plastic region mobility that could allow for predictions of their position in future structures based on ligand shape and size.

subject areas

  • Aryl Hydrocarbon Hydroxylases
  • Biphenyl Compounds
  • Catalytic Domain
  • Crystallization
  • Crystallography, X-Ray
  • Escherichia coli Proteins
  • Imidazoles
  • Ligands
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Secondary
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Identity

PubMed Central ID

  • PMC2764533

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi9003765

PubMed ID

  • 19397311
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Additional Document Info

start page

  • 4762

end page

  • 4771

volume

  • 48

issue

  • 22

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