9kw4

Crystal structure of CYP105A1 R84A and miconazole complex

spinqualitylabelsall models 9kw4, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9kw4 is a 1 chain structure with sequence from Streptomyces griseolus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: A1L6X, HEM, TRS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CPXE_STRGO Publication Abstract from PubMed Cytochrome P450 (CYP) enzymes bind a heme group that acts as a catalytic center. Inhibition mechanisms in CYP enzymes have been studied extensively by biochemical and structural analyses. Noncompetitive inhibitors are generally believed to bind to allosteric sites remote from the active site to form enzyme-substrate-inhibitor (ESI) complexes. Docking simulations predict the binding sites of noncompetitive inhibitors to CYP enzymes, but to date, there has been no experimental structural verification of ESI complexes formed by CYP enzymes. We performed biochemical and structural analyses of CYP105A1 using the imidazole-containing inhibitors ketoconazole, lanoconazole, and miconazole. Enzyme inhibition analyses demonstrated that ketoconazole and miconazole act as competitive inhibitors, whereas lanoconazole acts as a noncompetitive inhibitor of CYP105A1. The obtained X-ray structures of enzyme-inhibitor (EI) complexes showed that lanoconazole can bind in various orientations to the heme iron compared with ketoconazole and miconazole. We also determined the X-ray structure of an ESI complex comprising CYP105A1, diclofenac, and lanoconazole. This structure shows that lanoconazole binds to the heme iron and that diclofenac closely interacts with the bound lanoconazole, but it is positioned distant from the heme group. Quantum mechanical calculations indicate that Cl-pi and electrostatic interactions between diclofenac and lanoconazole, and electrostatic interactions between diclofenac and positively charged arginine residues, stabilize the formation of the ESI complex. Based on these results, we propose a mechanism for cooperative inhibition between a substrate and an apparent noncompetitive inhibitor. Cooperative inhibition in cytochrome P450 between a substrate and an apparent noncompetitive inhibitor.,Hirano Y, Yoneda S, Yasuda K, Kurita N, Kawagoe F, Mikami B, Takita T, Yasukawa K, Ikushiro S, Takimoto-Kamimura M, Kittaka A, Sakaki T, Tamada T J Biol Chem. 2025 Apr 15;301(6):108513. doi: 10.1016/j.jbc.2025.108513. PMID:40246023 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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