3tda

Competitive replacement of thioridazine by prinomastat in crystals of cytochrome P450 2D6

spinqualitylabelsall models 3tda, resolution 2.67Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3tda is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HEM, PN0, ZN Related: 3qm4 Gene: CYP2D6, CYP2DL1 (HUMAN) Activity: Unspecific monooxygenase, with EC number 1.14.14.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CP2D6_HUMAN] Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants. Publication Abstract from PubMed 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 piperadine moiety of thioridazine forms a charge stabilized hydrogen bond with Asp301 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 Glu222. Incubation of the crystalline open thioridazine complex with alternative ligands, prinomastat, quinidine, quinine or ajmalicine displaced thioridazine. Quinine and ajmalicine formed charge stabilized hydrogen bonds with Glu216, whereas the protonated nitrogen of quinidine is equidistant from Asp301 and Glu216 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 Glu216 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 following replacement of thioridazine with alternative compounds. Contributions of Ionic Interactions and Protein Dynamics to Cytochrome P450 2D6 (CYP2D6)Substrate and Inhibitor Binding.,Wang A, Stout CD, Zhang Q, Johnson EF J Biol Chem. 2015 Jan 1. pii: jbc.M114.627661. PMID:25555909 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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