1e9x
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CYTOCHROME P450 14 ALPHA-STEROL DEMETHYLASE (CYP51) FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH 4-PHENYLIMIDAZOLE
OverviewOverview
Cytochrome P450 14alpha-sterol demethylases (CYP51) are essential enzymes, in sterol biosynthesis in eukaryotes. CYP51 removes the 14alpha-methyl, group from sterol precursors such as lanosterol, obtusifoliol, dihydrolanosterol, and 24(28)-methylene-24,25-dihydrolanosterol., Inhibitors of CYP51 include triazole antifungal agents fluconazole and, itraconazole, drugs used in treatment of topical and systemic mycoses. The, 2.1- and 2.2-A crystal structures reported here for 4-phenylimidazole- and, fluconazole-bound CYP51 from Mycobacterium tuberculosis (MTCYP51) are the, first structures of an authentic P450 drug target. MTCYP51 exhibits the, P450 fold with the exception of two striking differences-a bent I helix, and an open conformation of BC loop-that define an active site-access, channel running along the heme plane perpendicular to the direction, observed for the substrate entry in P450BM3. Although a channel analogous, to that in P450BM3 is evident also in MTCYP51, it is not open at the, surface. The presence of two different channels, with one being open to, the surface, suggests the possibility of conformationally regulated, substrate-in/product-out openings in CYP51. Mapping mutations identified, in Candida albicans azole-resistant isolates indicates that azole, resistance in fungi develops in protein regions involved in orchestrating, passage of CYP51 through different conformational stages along the, catalytic cycle rather than in residues directly contacting fluconazole., These new structures provide a basis for rational design of new, more, efficacious antifungal agents as well as insight into the molecular, mechanism of P450 catalysis.
About this StructureAbout this Structure
1E9X is a Single protein structure of sequence from Mycobacterium tuberculosis with HEM and PIM as ligands. Structure known Active Sites: HEM and PIM. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of cytochrome P450 14alpha -sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors., Podust LM, Poulos TL, Waterman MR, Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3068-73. PMID:11248033
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