3QM4

Human Cytochrome P450 (CYP) 2D6 - Prinomastat Complex

Summary for 3QM4

• Entry DOI: 10.2210/pdb3qm4/pdb
• Related: 2f9q
• Descriptor: Cytochrome P450 2D6, PROTOPORPHYRIN IX CONTAINING FE, Prinomastat, ... (5 entities in total)
• Functional Keywords: cyp2d6, p450 2d6, p450, monooxygenase, prinomastat, heme, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P10635
• Total number of polymer chains: 2
• Total formula weight: 109599.81

Authors

Wang, A.,Stout, C.D.,Johnson, E.F. (deposition date: 2011-02-03, release date: 2012-02-15, Last modification date: 2023-09-13)

Primary citation

Wang, A.,Savas, U.,Hsu, M.H.,Stout, C.D.,Johnson, E.F.
Crystal Structure of Human Cytochrome P450 2D6 with Prinomastat Bound.
J.Biol.Chem., 287:10834-10843, 2012

PubMed 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.

PubMed: 22308038
DOI: 10.1074/jbc.M111.307918

Experimental method

X-RAY DIFFRACTION (2.85 Å)