1x8v
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| , resolution 1.55Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Gene: | cyp51 (Mycobacterium tuberculosis) | ||||||
| Activity: | Sterol 14-demethylase, with EC number 1.14.13.70 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Estriol-bound and ligand-free structures of sterol 14alpha-demethylase (CYP51)
OverviewOverview
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 StructureAbout this Structure
1X8V is a Single protein structure of sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.
ReferenceReference
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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