1h5z

From Proteopedia

Revision as of 14:24, 5 November 2007

CYTOCHROME P450 14 ALPHA-STEROL DEMETHYLASE (CYP51) FROM MYCOBACTERIUM TUBERCULOSIS IN FERRIC LOW-SPIN STATE

Overview

Sterol 14alpha-demethylases (CYP51) are essential enzymes in sterol, biosynthesis in eukaryotes and drug targets in antifungal therapy. Here, we report CYP51 structures in ligand-free and estriol bound forms. Using, estriol as a probe, we determined orientation of the substrate in the, active site, elucidated protein contacts with the invariant 3beta-hydroxy, group of a sterol, and identified F78 as a key discriminator between, 4alpha-methylated and 4alpha,beta-dimethylated substrates. Analysis of, CYP51 dynamics revealed that the C helix undergoes helix-coil transition, upon binding and dissociation of a ligand. Loss of helical structure of, the C helix in the ligand-free form results in an unprecedented opening of, the substrate binding site. Upon binding of estriol, the BC loop loses, contacts with molecular surface and tends to adopt a closed conformation., A mechanism for azole resistance in the yeast pathogen Candida albicans, associated with mutations in the ERG11 gene encoding CYP51 is suggested, based on CYP51 protein dynamics.

About this Structure

1H5Z is a Single protein structure of sequence from Mycobacterium tuberculosis with FE2 and HEM as ligands. Active as Sterol 14-demethylase, with EC number 1.14.13.70 Structure known Active Site: HEM. Full crystallographic information is available from OCA.

Reference

Estriol bound and ligand-free structures of sterol 14alpha-demethylase., Podust LM, Yermalitskaya LV, Lepesheva GI, Podust VN, Dalmasso EA, Waterman MR, Structure. 2004 Nov;12(11):1937-45. PMID:15530358

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