1h5z
From Proteopedia
| Line 4: | Line 4: | ||
==Overview== | ==Overview== | ||
| - | Sterol 14alpha-demethylases (CYP51) are essential enzymes in sterol | + | 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== | ==About this Structure== | ||
| Line 15: | Line 15: | ||
[[Category: Sterol 14-demethylase]] | [[Category: Sterol 14-demethylase]] | ||
[[Category: Arase, M.]] | [[Category: Arase, M.]] | ||
| - | [[Category: Podust, L | + | [[Category: Podust, L M.]] |
| - | [[Category: Waterman, M | + | [[Category: Waterman, M R.]] |
[[Category: FE2]] | [[Category: FE2]] | ||
[[Category: HEM]] | [[Category: HEM]] | ||
| Line 27: | Line 27: | ||
[[Category: sterol biosynthesis]] | [[Category: sterol biosynthesis]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:57:53 2008'' |
Revision as of 10:57, 21 February 2008
|
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 and as ligands. Active as Sterol 14-demethylase, with EC number 1.14.13.70 Known structural/functional Site: . 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
Page seeded by OCA on Thu Feb 21 12:57:53 2008
