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A structural snapshot of CYP2B4 in complex with paroxetine provides insights into ligand binding and clusters of conformational states

Academic Article
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Overview

authors

  • Shah, M. B.
  • Kufareva, I.
  • Pascual, J.
  • Zhang, Qinghai
  • Stout, C. David
  • Halpert, J. R.

publication date

  • July 2013

journal

  • Journal of Pharmacology and Experimental Therapeutics  Journal

abstract

  • An X-ray crystal structure of CYP2B4 in complex with the drug paroxetine [(3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine] was solved at 2.14 Å resolution. The structure revealed a conformation intermediate to that of the recently solved complex with amlodipine and that of the more compact complex with 4-(4-chlorophenyl)imidazole in terms of the placement of the F-G cassette. Moreover, comparison of the new structure with 15 previously solved structures of CYP2B4 revealed some new insights into the determinants of active-site size and shape. The 2B4-paroxetine structure is nearly superimposable on a previously solved closed structure in a ligand-free state. Despite the overall conformational similarity among multiple closed structures, the active-site cavity volume of the paroxetine complex is enlarged. Further analysis of the accessible space and binding pocket near the heme reveals a new subchamber that resulted from the movement of secondary structural elements and rearrangements of active-site side chains. Overall, the results from the comparison of all 16 structures of CYP2B4 demonstrate a cluster of protein conformations that were observed in the presence or absence of various ligands.

subject areas

  • Amino Acid Substitution
  • Animals
  • Antidepressive Agents, Second-Generation
  • Aryl Hydrocarbon Hydroxylases
  • Catalytic Domain
  • Crystallography, X-Ray
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System
  • Databases, Protein
  • Enzyme Inhibitors
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Mutant Proteins
  • Paroxetine
  • Peptide Fragments
  • Protein Binding
  • Protein Structure, Secondary
  • Rabbits
  • Rats
  • Recombinant Proteins
  • Serotonin Uptake Inhibitors
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Identity

PubMed Central ID

  • PMC3684837

International Standard Serial Number (ISSN)

  • 0022-3565

Digital Object Identifier (DOI)

  • 10.1124/jpet.113.204776

PubMed ID

  • 23633618
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Additional Document Info

start page

  • 113

end page

  • 120

volume

  • 346

issue

  • 1

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