4uym

Crystal structure of sterol 14-alpha demethylase (CYP51B) from a pathogenic filamentous fungus Aspergillus fumigatus in complex with voriconazole

spinqualitylabelsall models 4uym, resolution 2.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4uym is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HEM, VOR Related: 4uyl Activity: Sterol 14-demethylase, with EC number 1.14.13.70 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum Publication Abstract from PubMed Aspergillus fumigatus is the opportunistic fungal pathogen that predominantly affects the immunocompromised population and causes 600,000 deaths per year. The cytochrome P450 (CYP) 51 inhibitor voriconazole is currently the drug of choice, yet the treatment efficiency remains low, calling for rational development of more efficient agents. A. fumigatus has two CYP51 genes, CYP51A and CYP51B, which share 59% amino acid sequence identity. CYP51B is expressed constitutively, while gene CYP51A is reported to be inducible. We expressed, purified, and characterized A. fumigatus CYP51B, including determination of its substrate preferences, catalytic parameters, inhibition, and X-ray structure in complexes with voriconazole and the experimental inhibitor (R)-N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadia zol-2-yl)benzamide (VNI). The enzyme demethylated its natural substrate eburicol and the plant CYP51 substrate obtusifoliol at steady-state rates of 17 and 16 min-1, respectively, but did not metabolize lanosterol, and the topical antifungal drug miconazole was the strongest inhibitor that we identified. The X-ray crystal structures displayed high overall similarity of A. fumigatus CYP51B to CYP51 orthologs from other biological kingdoms but revealed phylum-specific differences relevant to enzyme catalysis and inhibition. The complex with voriconazole provides an explanation for the potency of this relatively small molecule, while the complex with VNI outlines a direction for further enhancement of the efficiency of this new inhibitory scaffold to treat humans afflicted with filamentous fungal infections. Structure-functional Characterization of Cytochrome P450 Sterol 14alpha-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs.,Hargrove TY, Wawrzak Z, Lamb DC, Guengerich FP, Lepesheva GI J Biol Chem. 2015 Aug 12. pii: jbc.M115.677310. PMID:26269599 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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