Crystal structures of Trypanosoma brucei sterol 14α-demethylase and implications for selective treatment of human infections

Simple item page
dc.creatorLepesheva, Galina I.
dc.creatorPark, Hee Won
dc.creatorHargrove, Tatiana Y.
dc.creatorVanhollebeke, Benoit
dc.creatorWawrzak, Zdzislaw
dc.creatorHarp, Joel M.
dc.creatorSundaramoorthy, Munirathinam
dc.creatorNes, W. David (TTU)
dc.creatorPays, Etienne
dc.creatorChaudhuri, Minu
dc.creatorVillalta, Fernando
dc.creatorWaterman, Michael R.
dc.date.accessioned2023-09-01T16:40:12Z
dc.date.available2023-09-01T16:40:12Z
dc.date.issued2010
dc.descriptioncc-by
dc.description.abstractSterol 14α-demethylase (14DM, the CYP51 family of cytochrome P450) is an essential enzyme in sterol biosynthesis in eukaryotes. It serves as a major drug target for fungal diseases and can potentially become a target for treatment of human infections with protozoa. Here we present 1.9 Å resolution crystal structures of 14DM from the protozoan pathogen Trypanosoma brucei, ligand-free and complexed with a strong chemically selected inhibitor N-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3, 4-oxadi-azol-2-yl)benzamide that we previously found to produce potent antiparasitic effects in Trypanosomatidae. This is the first structure of a eukaryotic microsomal 14DM that acts on sterol biosynthesis, and it differs profoundly from that of the water-soluble CYP51 family member from Mycobacterium tuberculosis, both in organization of the active site cavity and in the substrate access channel location. Inhibitor binding does not cause large scale conformational rearrangements, yet induces unanticipated local alterations in the active site, including formation of a hydrogen bond network that connects, via the inhibitor amide group fragment, two remote functionally essential protein segments and alters the heme environment. The inhibitor binding mode provides a possible explanation for both its functionally irreversible effect on the enzyme activity and its selectivity toward the14DM from human pathogens versus the human 14DM ortholog. The structures shed new light on 14DM functional conservation and open an excellent opportunity for directed design of novel antiparasitic drugs. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
dc.identifier.citationLepesheva, G.I., Park, H.-W., Hargrove, T.Y., Vanhollebeke, B., Wawrzak, Z., Harp, J.M., Sundaramoorthy, M., Nes, W.D., Pays, E., Chaudhuri, M., Villalta, F., & Waterman, M.R.. 2010. Crystal structures of Trypanosoma brucei sterol 14α-demethylase and implications for selective treatment of human infections. Journal of Biological Chemistry, 285(3). https://doi.org/10.1074/jbc.M109.067470
dc.identifier.urihttps://doi.org/10.1074/jbc.M109.067470
dc.identifier.urihttps://hdl.handle.net/2346/95940
dc.language.isoeng
dc.titleCrystal structures of Trypanosoma brucei sterol 14α-demethylase and implications for selective treatment of human infections
dc.typeArticle

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
nes_article.pdf
Size:
2.01 MB
Format:
Adobe Portable Document Format
Description:
Main article with TTU Libraries cover page
Download

Collections

Faculty Research