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Crystal structure of the Trypanosoma cruzi trypanothione reductase·mepacrine complex
Author(s) -
Jacoby Elke M.,
Schlichting Ilme,
Lantwin Christina B.,
Kabsch Wolfgang,
KrauthSiegel R. Luise
Publication year - 1996
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/(sici)1097-0134(199601)24:1<73::aid-prot5>3.0.co;2-p
Subject(s) - mepacrine , active site , stereochemistry , chemistry , binding site , sulfonamide , trypanosoma , biochemistry , enzyme , biology , virology , malaria , immunology
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 Å 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. © 1996 Wiley‐Liss, Inc.