Active site of trypanothione reductase. A target for rational drug design

William N. Hunter, Susan Bailey, Jarjis Habash, Stephen J. Harrop, John R. Helliwell, Tamara Aboagye-Kwarteng, Keith Smith, Alan H. Fairlamb

Research output: Contribution to journalArticlepeer-review

118 Citations (Scopus)


The X-ray crystal structure of the enzyme trypanothione reductase, isolated from the trypanosomatid organism Crithidia fasciculata, has been solved by molecular replacement. The search model was the crystal structure of human glutathione reductase that shares approximately 40% sequence identity. The trypanosomal enzyme crystallizes in the tetragonal space group P41 with unit cell lengths of a = 128·9 A ̊ and c = 92·3 A ̊. The asymmetric unit consists of a homodimer of approximate molecular mass 108 kDa. We present the structural detail of the active site as derived from the crystallographic model obtained at an intermediate stage of the analysis using diffraction data to 2·8 Å resolution with an R-factor of 23·2%. This model has root-mean-square deviations from ideal geometry of 0·026 Å for bond lengths and 4·7 ° for bond angles. The trypanosomid enzyme assumes a similar biological function to glutathione reductase and, although similar in topology to human glutathione reductase, has an enlarged active site and a number of amino acid differences, steric and electrostatic, which allows it to process only the unique substrate trypanothione and not glutathione. This protein represents a prime target for chemotherapy of several debilitating tropical diseases caused by protozoan parasites belonging to the genera Trypanosoma and Leishmania. The structural differences between the parasite and host enzymes and their substrates thus provides a rational basis for the design of new drugs active against trypanosomes. In addition, our model explains the results of site-directed mutagenesis experiments, carried out on recombinant trypanothione reductase and glutathione reductases, designed by consideration of the crystal structure of human glutathione reductase.

Original languageEnglish
Pages (from-to)322-333
Number of pages12
JournalJournal of Molecular Biology
Issue number1
Publication statusPublished - 5 Sept 1992


  • crystal structure
  • enzyme specificity
  • glutathione reductase
  • molecular replacement
  • trypanothione reductase

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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