Open AccessSubstrate interactions between trypanothione reductase and N 1 ‐glutathionylspermidine disulphide at 0.28‐nm resolution
Author(s) -
BAILEY Sue,
SMITH Keith,
FAIRLAMB Alan H.,
HUNTER William N.
Publication year - 1993
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1111/j.1432-1033.1993.tb17734.x
Subject(s) - stereochemistry , active site , hydrogen bond , chemistry , moiety , substrate (aquarium) , crithidia fasciculata , crystallography , enzyme , biochemistry , biology , organic chemistry , molecule , ecology
The enzyme trypanothione reductase has been identified as a prime target for the rational design of inhibitors which may have clinical use in the treatment of tropical diseases caused by the genera Trypanosoma and Leishmania . To aid the design or identification of new inhibitors of this enzyme we have elucidated the structural detail of a trypanothione reductase complexed with one of the naturally occurring substrates, N 1 ‐glutathionylspermidine disulphide, by single‐crystal X‐ray diffraction methods at 0.28‐nm resolution. The model for the Crithidia fasciculata enzyme‐substrate complex has an R ‐factor of 14.8% and root‐mean‐square deviations of 0.0015 nm and 3.3° on bond lengths and angles respectively. Hydrogen bonding and van der Waals interactions between the enzyme and substrate are dominated by the amino acid side chains. The substrate binds in a rigid active site such that one glutathione moiety is in a V‐shape, the other in an extended conformation. One spermidine moiety binds closely to a hydrophobic patch in the active site formed by a tryptophan and a methionine. Distances between the methionine Sδ and the terminal N of this spermidine suggest that a hydrogen bond may supplement the hydrophobic interactions in this part of the active site.