Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Crystal structure of human cytochrome p450 2d6 with prinomastat bound

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Wang, A.
  • Savas, U.
  • Hsu, M. H.
  • Stout, C. David
  • Johnson, Eric

publication date

  • March 2012

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Human cytochrome P450 2D6 contributes to the metabolism of >15% of drugs used in clinical practice. This study determined the structure of P450 2D6 complexed with a substrate and potent inhibitor, prinomastat, to 2.85 Å resolution by x-ray crystallography. Prinomastat binding is well defined by electron density maps with its pyridyl nitrogen bound to the heme iron. The structure of ligand-bound P450 2D6 differs significantly from the ligand-free structure reported for the P450 2D6 Met-374 variant (Protein Data Bank code 2F9Q). Superposition of the structures reveals significant differences for β sheet 1, helices A, F, F', G", G, and H as well as the helix B-C loop. The structure of the ligand complex exhibits a closed active site cavity that conforms closely to the shape of prinomastat. The closure of the open cavity seen for the 2F9Q structure reflects a change in the direction and pitch of helix F and introduction of a turn at Gly-218, which is followed by a well defined helix F' that was not observed in the 2F9Q structure. These differences reflect considerable structural flexibility that is likely to contribute to the catalytic versatility of P450 2D6, and this new structure provides an alternative model for in silico studies of substrate interactions with P450 2D6.

subject areas

  • Catalytic Domain
  • Crystallography, X-Ray
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Enzyme Inhibitors
  • Humans
  • Ligands
  • Models, Molecular
  • Organic Chemicals
  • Protein Binding
scroll to property group menus

Identity

PubMed Central ID

  • PMC3322812

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M111.307918

PubMed ID

  • 22308038
scroll to property group menus

Additional Document Info

start page

  • 10834

end page

  • 10843

volume

  • 287

issue

  • 14

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support