Crystal structure of sterol 14alpha-demethylase (CYP51) from Trypanosoma cruzi in complex with an inhibitor VNF ((4-(4-chlorophenyl)-N-[2-(1H-imidazol-1-yl)-1-phenylethyl]benzamide)
3ksw 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.
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Trypanosoma cruzi causes Chagas disease (American trypanosomiasis), which threatens the lives of millions of people and remains incurable in its chronic stage. The antifungal drug posaconazole that blocks sterol biosynthesis in the parasite is the only compound entering clinical trials for the chronic form of this infection. Crystal structures of the drug target enzyme, Trypanosoma cruzi sterol 14alpha-demethylase (CYP51), complexed with posaconazole, another antifungal agent fluconazole and an experimental inhibitor, (R)-4'-chloro-N-(1-(2,4-dichlorophenyl)-2-(1H-imid-azol-1-yl)ethyl)bipheny l-4-carboxamide (VNF), allow prediction of important chemical features that enhance the drug potencies. Combined with comparative analysis of inhibitor binding parameters, influence on the catalytic activity of the trypanosomal enzyme and its human counterpart, and their cellular effects at different stages of the Trypanosoma cruzi life cycle, the structural data provide a molecular background to CYP51 inhibition and azole resistance and enlighten the path for directed design of new, more potent and selective drugs to develop an efficient treatment for Chagas disease.
Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi.,Lepesheva GI, Hargrove TY, Anderson S, Kleshchenko Y, Furtak V, Wawrzak Z, Villalta F, Waterman MR J Biol Chem. 2010 Aug 13;285(33):25582-90. Epub 2010 Jun 8. PMID:20530488[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑Lepesheva GI, Hargrove TY, Anderson S, Kleshchenko Y, Furtak V, Wawrzak Z, Villalta F, Waterman MR. Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi. J Biol Chem. 2010 Aug 13;285(33):25582-90. Epub 2010 Jun 8. PMID:20530488 doi:10.1074/jbc.M110.133215
