The crystal structure of trypanothione reductase from the human pathogen Trypanosoma cruzi at 2.3 Å resolution

TY - JOUR

T1 - The crystal structure of trypanothione reductase from the human pathogen Trypanosoma cruzi at 2.3 Å resolution

AU - Zhang, Yihong

AU - Bond, Charles S.

AU - Bailey, Susan

AU - Cunningham, Mark L.

AU - Fairlamb, Alan H.

AU - Hunter, William N.

PY - 1996/1

Y1 - 1996/1

N2 - Trypanothione reductase (TR) is an NADPH-dependent flavoprotein unique to protozoan parasites from the genera Trypanosoma and Leishmania and is an important target for the design of improved trypanocidal drugs. We present details of the structure of TR from the human pathogen Trypanosoma cruzi, the agent responsible for Chagas' disease or South American trypanosomiasis. The structure has been solved by molecular replacement, using as the starting model the structure of the enzyme from the nonpathogenic Crithidia fasciculata, and refined to an R-factor of 18.9% for 53,868 reflections with F ≥ σF between 8.0 and 2.3 Å resolution. The model comprises two subunits (968 residues), two FAD prosthetic groups, two maleate ions, and 419 water molecules. The accuracy and geometry of the enzyme model is improved with respect to the C. fasciculata enzyme model. The new structure is described and specific features of the enzyme involved in substrate interactions are compared with previous models of TR and related glutathione reductases from human and Escherichia coli. Structural differences at the edge of the active sites suggest an explanation for the differing specificities toward glutathionylspermidine disulfide.

AB - Trypanothione reductase (TR) is an NADPH-dependent flavoprotein unique to protozoan parasites from the genera Trypanosoma and Leishmania and is an important target for the design of improved trypanocidal drugs. We present details of the structure of TR from the human pathogen Trypanosoma cruzi, the agent responsible for Chagas' disease or South American trypanosomiasis. The structure has been solved by molecular replacement, using as the starting model the structure of the enzyme from the nonpathogenic Crithidia fasciculata, and refined to an R-factor of 18.9% for 53,868 reflections with F ≥ σF between 8.0 and 2.3 Å resolution. The model comprises two subunits (968 residues), two FAD prosthetic groups, two maleate ions, and 419 water molecules. The accuracy and geometry of the enzyme model is improved with respect to the C. fasciculata enzyme model. The new structure is described and specific features of the enzyme involved in substrate interactions are compared with previous models of TR and related glutathione reductases from human and Escherichia coli. Structural differences at the edge of the active sites suggest an explanation for the differing specificities toward glutathionylspermidine disulfide.

KW - Disulfide oxidoreductase

KW - FAD

KW - Glutathione reductase

KW - NADPH

KW - Trypanosomiasis

KW - Trypanothione reductase

KW - X-ray structure

UR - https://www.scopus.com/pages/publications/0030045604

U2 - 10.1002/pro.5560050107

DO - 10.1002/pro.5560050107

M3 - Article

C2 - 8771196

AN - SCOPUS:0030045604

SN - 0961-8368

VL - 5

SP - 52

EP - 61

JO - Protein Science

JF - Protein Science

IS - 1

ER -