Crystal structure of Trypanosoma cruzi glyceraldehyde‐3‐phosphate dehydrogenase complexed with an analogue of 1,3‐bisphospho‐d‐glyceric acid

Abstract

We report here the first crystal structure of a stable isosteric analogue of 1,3-bisphospho-D-glyceric acid (1, bound to the catalytic domain of Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) in which the two phosphoryl moieties interact with Arg249. This complex possibly illustrates a step of the catalytic process by which Arg249 may induce compression of the product formed, allowing its expulsion from the active site. Structural modifications were introduced into this isosteric analogue and the respective inhibitory effects of the resulting diphosphorylated compounds on T. cruzi and Trypanosoma brucei gGAPDHs were investigated by enzymatic inhibition studies, fluorescence spectroscopy, sitedirected mutagenesis, and molecular modelling. Despite the high homology between the two trypanomastid gGAPDHs (> 95%), we have identified specific interactions that could be used to design selective irreversible inhibitors against T. cruzi gGAPDH.

Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: Kinetic and structural studies

“…X-ray structural data is very useful to reveal three-dimensional (3D) molecular interactions involved in enzyme inhibitor complexes. 34,35 A careful analysis of the crystallographic complex between the inhibitor 4 and SmPNP (PDB ID 3DJF) indicates that this might be a result of the H-bonding to Tyr202 (Fig. 2).…”

Structure-Based Drug Discovery for Tropical Diseases

“…Therefore, the vital dependence on glycolysis as the main source of energy for the parasites, combined to distinct molecular properties when compared with their human counterparts makes the glycolytic enzymes attractive targets for drug design. Structure-and ligand-based approa- ches on enzymes of the carbohydrate metabolism pathway have identified several promising inhibitors, as well as shed light on the structural basis for selective inhibition [102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117].…”

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

“…1GYP [119]; 1A7K [120]; 1GYQ [121] 1YWG [122]; 2B4R, 2B4T [123] 2X0N [124]; 4P8R [125] 1K3T [126]; 1ML3 [127]; 1QXS [128]; 3IDS [129] Glycerol-3-phosphate dehydrogenase (GPDH) 1EVY, 1EVZ [130];1JDJ, 1M66, 1M67, 1N1G [131]; 1N1E [132] Glyoxalase I (GLO1) 2C21 [133] Glyoxalase II (GLO2) 2P18, 2P1E [134] GMP synthetase (GMPS) 3UOW [135] Guanylate kinase (GK) 1Z6G [136] Heat shock protein 90 (HSP90) 3H80 [137], 3Q5J, 3Q5K, 3Q5L, [138]; 3U67 [139] …”