4WNU

Human Cytochrome P450 2D6 Quinidine Complex

Summary for 4WNU

• Entry DOI: 10.2210/pdb4wnu/pdb
• Related: 2F9Q 3QM4 3TBG 3TDA 4WNT 4WNV 4WNW
• Descriptor: Cytochrome P450 2D6, PROTOPORPHYRIN IX CONTAINING FE, Quinidine, ... (7 entities in total)
• Functional Keywords: cyp2d6, p450 2d6, cytochrome p450, monooxygenase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 220246.40

Authors

Wang, A.,Stout, C.D.,Johnson, E.F. (deposition date: 2014-10-14, release date: 2015-01-14, Last modification date: 2023-09-27)

Primary citation

Wang, A.,Stout, C.D.,Zhang, Q.,Johnson, E.F.
Contributions of Ionic Interactions and Protein Dynamics to Cytochrome P450 2D6 (CYP2D6) Substrate and Inhibitor Binding.
J.Biol.Chem., 290:5092-5104, 2015

PubMed Abstract: P450 2D6 contributes significantly to the metabolism of >15% of the 200 most marketed drugs. Open and closed crystal structures of P450 2D6 thioridazine complexes were obtained using different crystallization conditions. The protonated piperidine moiety of thioridazine forms a charge-stabilized hydrogen bond with Asp-301 in the active sites of both complexes. The more open conformation exhibits a second molecule of thioridazine bound in an expanded substrate access channel antechamber with its piperidine moiety forming a charge-stabilized hydrogen bond with Glu-222. Incubation of the crystalline open thioridazine complex with alternative ligands, prinomastat, quinidine, quinine, or ajmalicine, displaced both thioridazines. Quinine and ajmalicine formed charge-stabilized hydrogen bonds with Glu-216, whereas the protonated nitrogen of quinidine is equidistant from Asp-301 and Glu-216 with protonated nitrogen H-bonded to a water molecule in the access channel. Prinomastat is not ionized. Adaptations of active site side-chain rotamers and polypeptide conformations were evident between the complexes, with the binding of ajmalicine eliciting a closure of the open structure reflecting in part the inward movement of Glu-216 to form a hydrogen bond with ajmalicine as well as sparse lattice restraints that would hinder adaptations. These results indicate that P450 2D6 exhibits sufficient elasticity within the crystal lattice to allow the passage of compounds between the active site and bulk solvent and to adopt a more closed form that adapts for binding alternative ligands with different degrees of closure. These crystals provide a means to characterize substrate and inhibitor binding to the enzyme after replacement of thioridazine with alternative compounds.

PubMed: 25555909
DOI: 10.1074/jbc.M114.627661

Experimental method

X-RAY DIFFRACTION (2.26 Å)