Structural basis of human CYP51 inhibition by antifungal azoles.

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  • Author(s): Strushkevich N;Strushkevich N; Usanov SA; Park HW
  • Source:
    Journal of molecular biology [J Mol Biol] 2010 Apr 09; Vol. 397 (4), pp. 1067-78. Date of Electronic Publication: 2010 Feb 10.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 2985088R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1089-8638 (Electronic) Linking ISSN: 00222836 NLM ISO Abbreviation: J Mol Biol Subsets: MEDLINE
    • Publication Information:
      Publication: Amsterdam : Elsevier
      Original Publication: 1959- : London : Academic Press
    • Subject Terms:
      Cytochrome P-450 Enzyme Inhibitors*; Cytochrome P-450 Enzyme System/*chemistry ; Econazole/*pharmacology ; Enzyme Inhibitors/*pharmacology ; Ketoconazole/*pharmacology; Bacterial Proteins/chemistry ; Catalytic Domain ; Crystallography, X-Ray ; Econazole/chemistry ; Econazole/metabolism ; Enzyme Inhibitors/metabolism ; Humans ; Ketoconazole/chemistry ; Ketoconazole/metabolism ; Models, Molecular ; Molecular Structure ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; Sterol 14-Demethylase
    • Abstract:
      The obligatory step in sterol biosynthesis in eukaryotes is demethylation of sterol precursors at the C14-position, which is catalyzed by CYP51 (sterol 14-alpha demethylase) in three sequential reactions. In mammals, the final product of the pathway is cholesterol, while important intermediates, meiosis-activating sterols, are produced by CYP51. Three crystal structures of human CYP51, ligand-free and complexed with antifungal drugs ketoconazole and econazole, were determined, allowing analysis of the molecular basis for functional conservation within the CYP51 family. Azole binding occurs mostly through hydrophobic interactions with conservative residues of the active site. The substantial conformational changes in the B' helix and F-G loop regions are induced upon ligand binding, consistent with the membrane nature of the protein and its substrate. The access channel is typical for mammalian sterol-metabolizing P450 enzymes, but is different from that observed in Mycobacterium tuberculosis CYP51. Comparison of the azole-bound structures provides insight into the relative binding affinities of human and bacterial P450 enzymes to ketoconazole and fluconazole, which can be useful for the rational design of antifungal compounds and specific modulators of human CYP51.
      ((c) 2010 Elsevier Ltd. All rights reserved.)
    • Grant Information:
      Canada Canadian Institutes of Health Research; United Kingdom Wellcome Trust
    • Molecular Sequence:
      PDB 3I3K; 3JUS; 3JUV
    • Accession Number:
      0 (Bacterial Proteins)
      0 (CYP51A1 protein, human)
      0 (Cytochrome P-450 Enzyme Inhibitors)
      0 (Enzyme Inhibitors)
      6Z1Y2V4A7M (Econazole)
      9035-51-2 (Cytochrome P-450 Enzyme System)
      EC 1.14.14.- (cytochrome P-450 CYP51, Mycobacterium tuberculosis)
      EC 1.14.14.154 (Sterol 14-Demethylase)
      R9400W927I (Ketoconazole)
    • Publication Date:
      Date Created: 20100213 Date Completed: 20100414 Latest Revision: 20191210
    • Publication Date:
      20240829
    • Accession Number:
      10.1016/j.jmb.2010.01.075
    • Accession Number:
      20149798