title: Crystal structure of the Trypanosoma cruzi trypanothione reductase.mepacrine complex.
abstract: The three-dimensional structure of the complex between Trypanosoma cruzi trypanothione reductase (TR) (EC 1.6.4.8) and the antiparasitic drug mepacrine (quinacrine) has been solved at 2.9 angstoms resolution. Mepacrine is a competitive inhibitor of TR but does not affect human glutathione reductase (GR), a closely related host enzyme. Of particular importance for inhibitor binding are four amino acid residues in the disulfide substrate-binding site of TR that are not conserved in human GR, namely, Glu-18 (Ala-34 in GR), Trp-21 (Arg-37), Ser-109 (Ile-113), and Met-113 (Asn-117). The acridine ring of mepacrine is fixed at the active site close to the hydrophobic wall formed by Trp-21 and Met-113. Specific pairwise interactions between functional groups of the drug and amino acid side chains include the ring nitrogen and Met-113, the chlorine atom and Trp-21, and the oxymethyl group and Ser-109. The alkylamino chain of mepacrine points into the inner region of the active site and is held in position by a solvent-mediated hydrogen bond to Glu-18. The structure of the complex shows for the first time the atomic interactions between TR and an inhibitory ligand. This is a crucial step towards the rational design of inhibitors that might be suited as drugs against Chagas' disease.
authors.affiliation: Institut für Biochemie II, Universität Heidelberg, Germany.
authors.forename: E M
authors.initials: EM
authors.lastname: Jacoby
authors.forename: I
authors.initials: I
authors.lastname: Schlichting
authors.forename: C B
authors.initials: CB
authors.lastname: Lantwin
authors.forename: W
authors.initials: W
authors.lastname: Kabsch
authors.forename: R L
authors.initials: RL
authors.lastname: Krauth-Siegel
mesh_terms: D000166:Acridines / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D011796:Quinacrine / Q000737:chemistry* / Q000494:pharmacology; D013379:Substrate Specificity; D014344:Trypanocidal Agents / Q000378:metabolism / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000166:Acridines; D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D011796:Quinacrine