4uhi

HUMAN STEROL 14-ALPHA DEMETHYLASE (CYP51) IN COMPLEX WITH VFV IN C121 SPACE GROUP

spinqualitylabelsall models 4uhi, resolution 2.04Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4uhi 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, VFV Related: 4uhl Activity: Sterol 14-demethylase, with EC number 1.14.13.70 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CP51A_HUMAN] Catalyzes C14-demethylation of lanosterol; it transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol. Publication Abstract from PubMed Rapidly multiplying cancer cells synthesize greater amounts of cholesterol to build their membranes. Cholesterol-lowering drugs (statins) are currently in clinical trials for anticancer chemotherapy. However, given at higher doses statins cause serious side effects by inhibiting the formation of other biologically important molecules derived from mevalonate. Sterol 14alpha-demethylase (CYP51), which acts 10 steps downstream, is potentially a more specific drug target because this portion of the pathway is fully committed to cholesterol production. However, screening a variety of commercial and experimental inhibitors of microbial CYP51 orthologs revealed that most of them (including all clinical antifungals) weakly inhibit human CYP51 activity, even if they display high apparent spectral binding affinity. Only one relatively potent compound, VFV ((R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3 ,4-oxadiazol-2-yl)benzamide), was identified. VFV has been further tested in cellular experiments and found to decrease proliferation of different cancer cell types. The crystal structures of human CYP51-VFV complexes (2.0 and 2.5 A) both display a 2:1 inhibitor/enzyme stoichiometry, provide molecular insights regarding a broader substrate profile, faster catalysis, and weaker susceptibility of human CYP51 to inhibition and outline directions for the development of more potent inhibitors. Human sterol 14alpha-demethylase (CYP51) as a target for anticancer chemotherapy: Towards structure-aided drug design.,Hargrove TY, Friggeri L, Wawrzak Z, Sivakumaran S, Yazlovitskaya EM, Hiebert SW, Guengerich FP, Waterman MR, Lepesheva GI J Lipid Res. 2016 Jun 16. pii: jlr.M069229. PMID:27313059 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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