Michael Waterman
Faculty Member
Last active: 2/12/2015

Estriol bound and ligand-free structures of sterol 14alpha-demethylase.

Podust LM, Yermalitskaya LV, Lepesheva GI, Podust VN, Dalmasso EA, Waterman MR
Structure. 2004 12 (11): 1937-45

PMID: 15530358 · DOI:10.1016/j.str.2004.08.009

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.

MeSH Terms (12)

Amino Acid Sequence Cytochrome P-450 Enzyme System Estriol Ligands Models, Molecular Molecular Probes Molecular Sequence Data Oxidoreductases Protein Conformation Sequence Homology, Amino Acid Sterol 14-Demethylase Substrate Specificity

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