January 2010

Don’t Sleep on This Structure

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Ligand-free trypanosomal 14α-demethylase (salmon) superposed with the related mycobacterial CYP51 (green).

Current treatments for trypanosome diseases like sleeping sickness often lack specificity and have severe side effects. Thus, newer, better drug targets are needed. Trypanosomal sterol 14α-demethylase (14DM), an essential enzyme in the production of membrane sterols, is a highly promising lead, as its fungal counterpart is a major drug target for treating fungal infections in humans. In this study, the authors solved 1.9 Å resolution crystal structures of 14DM from Trypanosoma brucei in both a native state and in a complex with the inhibitor VN1. Together, they provide the first structural insights into a eukaryotic microsomal 14DM. The structures show that the organization of the active site cavity and the location of the substrate access channel differ profoundly in 14DM compared with water-soluble members of the CYP51 family. VN1 binding does not cause large-scale conformational rearrangements, but it does induce local changes in the active site, including the formation of a hydrogen bond network connecting VN1 and two distant and functionally essential protein segments. The structural details of VN1 binding provides a possible explanation for both its selectivity toward trypanosomal 14DM and its potency, and it should provide an excellent template for designing novel parasite-specific drugs.

Crystal Structures of Trypanosoma brucei Sterol 14 alpha-demethylase and Implications for Selective Treatment of Human Infections 

Galina I. Lepesheva, Hee-Won Park, Tatiana Y. Hargrove, Benoit Vanhollebeke, Zdzislaw Wawrzak, Joel M. Harp, Munirathinam Sundaramoorthy, W. David Nes, Etienne Pays, Minu Chaudhuri, Fernando Villalta and Michael R. Waterman

J. Biol. Chem., published online Nov. 18, 2009 

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