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Crystal structure of cytochrome P450 14a-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors



Crystal structure of cytochrome P450 14a-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors



Proceedings of the National Academy of Sciences of the United States of America 98(6): 68-73



The 2.1 and 2.2 A crystal structures for 4-phenylimidazole- and fluconazole-bound cytochrome P450 14a-sterol demethylases (CYP51) from Mycobacterium tuberculosis (MTCYP51) are reported. CYP51 are essential enzymes in sterol biosynthesis in eukaryotes. MTCYP51 was found to exhibit the P450 fold with the exception of 2 striking differences: a bent I helix and an open conformation of BC loop. These differences defined 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 was evident also in MTCYP51, it was not open at the surface. These new structures provide an insight into the molecular mechanism of P450 catalysis and a basis for rational design of new, more efficacious antifungal agents.

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Accession: 009807330

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