1H5Z

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

Summary for 1H5Z

• Entry DOI: 10.2210/pdb1h5z/pdb
• Related: 1E9X 1EA1
• Descriptor: CYTOCHROME P450 51, PROTOPORPHYRIN IX CONTAINING FE, FE (II) ION, ... (4 entities in total)
• Functional Keywords: oxidoreductase, cytochrome p450, 14 alpha-sterol demethylase, ferric low-spin, sterol biosynthesis, monooxygenase, electron transport
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 1
• Total formula weight: 52171.66

Authors

Podust, L.M.,Arase, M.,Waterman, M.R. (deposition date: 2001-05-31, release date: 2003-10-03, Last modification date: 2023-12-13)

Primary citation

Podust, L.M.,Yermalitskaya, L.V.,Lepesheva, G.I.,Podust, V.N.,Dalmasso, E.A.,Waterman, M.R.
Estriol Bound and Ligand-Free Structures of Sterol 14Alpha-Demethylase.
Structure, 12:1937-, 2004

PubMed Abstract: 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.

PubMed: 15530358
DOI: 10.1016/J.STR.2004.08.009

Experimental method

X-RAY DIFFRACTION (2.05 Å)