4cka

STEROL 14-ALPHA DEMETHYLASE (CYP51)FROM TRYPANOSOMA CRUZI IN COMPLEX WITH (S)-1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl 4- isopropylphenylcarbamate (LFS)

spinqualitylabelsall models 4cka, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4cka is a 1 chain structure with sequence from Trypanosoma cruzi. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HEM, LFS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CP51_TRYCC] Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol (By similarity). Favors C4 dimethylated substrates, the substrate preference order is 24-methylenedihydrolanosterol > 24,25-dihydrolanosterol > lanosterol > obtusifoliol > norlanosterol. [UniProtKB:P0A512] Publication Abstract from PubMed Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14alpha-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of beta-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50 = 1.2 nM, vs (S)-2/(S)-3, EC50 = 1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs. Structural Basis for Rational Design of Inhibitors Targeting Trypanosoma cruzi Sterol 14alpha-Demethylase: Two Regions of the Enzyme Molecule Potentiate Its Inhibition.,Friggeri L, Hargrove TY, Rachakonda G, Williams AD, Wawrzak Z, Di Santo R, De Vita D, Waterman MR, Tortorella S, Villalta F, Lepesheva GI J Med Chem. 2014 Jul 29. PMID:25033013 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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