ABSTRACT
The structure of the glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) from Trypanosoma cruzi complexed with chalepin, a natural product from Pilocarpus spicatus, has been determined by X-ray crystallography to 1.95 A resolution. The structure is in the apo form without cofactors in the subunits of the tetrameric gGAPDH in the asymmetric unit. Unequivocal density corresponding to the inhibitor was clearly identified in one monomer. The final refined model of the complex shows extensive conformational changes when compared with the native structure. The mode of binding of chalepin to gGAPDH and its implications for inhibitor design are discussed.
Subject(s)
Furocoumarins/chemistry , Glyceraldehyde-3-Phosphate Dehydrogenases/chemistry , Microbodies/enzymology , Trypanosoma cruzi/enzymology , Animals , Crystallization , Crystallography, X-Ray , Furocoumarins/metabolism , Glyceraldehyde-3-Phosphate Dehydrogenases/genetics , Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism , Macromolecular Substances , Molecular Structure , Protein Binding , Structure-Activity Relationship , Trypanosoma cruzi/geneticsABSTRACT
A new purine, 1,3-dimethylisoguanine (1), has been isolated from the marine sponge Amphimedon viridis and identified by analysis of spectroscopic data. Compound 1 increased the contractions obtained by transmural electrical stimulation in the guinea pig longitudinal muscle/myenteric plexus in a dose-dependent manner.
