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Crystal structure of the Trypanosoma cruzi trypanothione reductase-mepacrine complex

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Schlichting,  Ilme
Emeritus Group Biophysics, Max Planck Institute for Medical Research, Max Planck Society;

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Kabsch,  Wolfgang
Emeritus Group Biophysics, Max Planck Institute for Medical Research, Max Planck Society;
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Jacoby, E. M., Schlichting, I., Lantwin, C. B., Kabsch, W., & Krauth-Siegel, R. L. (1996). Crystal structure of the Trypanosoma cruzi trypanothione reductase-mepacrine complex. Proteins: Structure, Function, and Genetics, 24(1), 73-80. doi:10.1002/(SICI)1097-0134(199601)24:1<73:AID-PROT5>3.0.CO;2-P.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0024-3CE7-2
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