An Improved Model of the Trypanosoma brucei CTP Synthetase Glutaminase Domain-Acivicin Complex.
The natural product acivicin inhibits the glutaminase activity of cytidine triphosphate (CTP) synthetase and is a potent lead compound for drug discovery in the area of neglected tropical diseases, specifically trypanosomaisis. A 2.1-Å-resolution crystal structure of the acivicin adduct with the glutaminase domain from Trypanosoma brucei CTP synthetase has been deposited in the RCSB Protein Data Bank (PDB) and provides a template for structure-based approaches to design new inhibitors. However, our assessment of that data identified deficiencies in the model. We now report an improved and corrected inhibitor structure with changes to the chirality at one position, the orientation and covalent structure of the isoxazoline moiety, and the location of a chloride ion in an oxyanion binding site that is exploited during catalysis. The model is now in agreement with established chemical principles and allows an accurate description of molecular recognition of the ligand and the mode of binding in a potentially valuable drug target.
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK.
Juliana
J
Oliveira de Souza
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK.
Alice
A
Dawson
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK.
William N
0000-0002-6019-3102
WN
Hunter
D001412:Bacillus subtilis / Q000201:enzymology; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020134:Catalytic Domain; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016480:Helicobacter pylori / Q000201:enzymology; D006860:Hydrogen Bonding; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D005723:gamma-Glutamyltransferase / Q000737:chemistry
D007555:Isoxazoles; D008024:Ligands; D014344:Trypanocidal Agents; D005723:gamma-Glutamyltransferase; D005972:Glutaminase; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase; C006303:acivicin
CTP synthetase; acivicin; glutaminase; structure-based drug discovery; trypanosomiasis