Structural complex of sterol 14α-demethylase (CYP51) with 14α-methylenecyclopropyl-Δ7-24, 25-dihydrolanosterol

Tatiana Y. Hargrove, Zdzislaw Wawrzak, Jialin Liu, Michael R. Waterman, W. David Nes, Galina I. Lepesheva*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    60 Scopus citations


    Sterol 14α-demethylase (CYP51) that catalyzes the removal of the 14α-methyl group from the sterol nucleus is an essential enzyme in sterol biosynthesis, a primary target for clinical and agricultural antifungal azoles and an emerging target for antitrypanosomal chemotherapy. Here, we present the crystal structure of Trypanosoma ( T ) brucei CYP51 in complex with the substrate analog 14α- methylenecyclopropyl-Δ7-24,25- dihydrolanosterol (MCP). This sterol binds tightly to all protozoan CYP51s and acts as a competitive inhibitor of F105-containing (plant-like) T. brucei and Leishmania ( L ) infantum orthologs, but it has a much stronger, mechanism-based inhibitory effect on I105-containing (animal/fungi-like) T. cruzi CYP51. Depicting substrate orientation in the conserved CYP51 binding cavity, the complex specifi es the roles of the contact amino acid residues and sheds new light on CYP51 substrate specifi city. It also provides an explanation for the effect of MCP on T. cruzi CYP51. Comparison with the ligand-free and azole-bound structures supports the notion of structural rigidity as the characteristic feature of the CYP51 substrate binding cavity, confi rming the enzyme as an excellent candidate for structure-directed design of new drugs, including mechanism-based substrate analog inhibitors.

    Original languageEnglish (US)
    Pages (from-to)311-320
    Number of pages10
    JournalJournal of lipid research
    Issue number2
    StatePublished - Feb 2012


    • Crystal structure
    • Cytochrome P450
    • Inhibition
    • Sterol biosynthesis
    • Sterol biosynthetic enzymes
    • Suicide substrates
    • Trypanosoma brucei
    • Trypanosoma cruzi

    ASJC Scopus subject areas

    • Biochemistry
    • Endocrinology
    • Cell Biology


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