3l4d | pdb_00003l4d

Crystal structure of sterol 14-alpha demethylase (CYP51) from Leishmania infantum in complex with fluconazole

spinqualitylabelsall models 3l4d, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3l4d is a 4 chain structure with sequence from Leishmania infantum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.75Å Ligands: HEM, N8E, TPF Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A2TEF2_LEIIN Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Leishmaniasis is a major health problem that affects populations of 88 countries worldwide, with no vaccine and only a few moderately effective drugs. Here we report structure/function characterization of sterol 14alpha-demethylase (CYP51) from Leishmania infantum. The enzyme catalyzes removal of the 14alpha-methyl group from sterol precursors. The reaction is essential for membrane biogenesis and therefore has great potential to become a target for antileishmanial chemotherapy. Although L. infantum CYP51 prefers C4-monomethylated sterol substrates, C4-norlanosterol and obtusifoliol (Vmax of 10 and 8 min-1, respectively), it is also found to 14alpha-demethylate C4-dimethylated lanosterol (Vmax=0.9 min-1) and C4-desmethylated 14alpha-methylzymosterol (Vmax =1.9 min-1). Binding parameters with six sterols were tested, the Kds ranging within 0.25-1.4 muM. Thus, L. infantum CYP51 is the first example of a plant-like sterol 14alpha-demethylase, where requirements toward the composition of the C4 atom substituents are not strict, indicative of possible branching in the postsqualene portion of sterol biosynthesis in the parasite. Comparative analysis of three CYP51 substrate binding cavities (Trypanosoma (T) brucei, T. cruzi and L. infantum) suggests that substrate preferences of plant- and fungal-like protozoan CYP51s largely depend on the differences in the enzyme active site topology. These minor structural differences are also likely to underlie CYP51 catalytic rates, drug susceptibility and can be used to design potent and specific inhibitors. Substrate preferences and catalytic parameters determined by structural characteristics of Sterol 14{alpha}-demethylase (CYP51) from Leishmania infantum.,Hargrove TY, Wawrzak Z, Liu J, Nes WD, Waterman MR, Lepesheva GI J Biol Chem. 2011 May 31. PMID:21632531 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cytochrome P450 3D structures

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