Journal article

Publication year: 2003

Pages: 893-907

Journal: Journal of Molecular Biology

Volume number: 328

Issue number: 4

ISSN: 0022-2836

eISSN: 1089-8638

DOI Link: https://doi.org/10.1016/S0022-2836(03)00347-4

Publisher: Elsevier

Abstract: 
The malarial parasite Plasmodium falciparum is known to be sensitive to oxidative stress, and thus the antioxidant enzyme glutathione reductase (GR; NADPH + GSSG + H+ reversible arrow NADP(+) + 2 GSH) has become an attractive drug target for antimalarial drug development. Here, we report the 2.6 Angstrom resolution crystal structure of P. falciparum GR. The homodimeric flavoenzyme is compared to the related human GR with focus on structural aspects relevant for drug design. The most pronounced differences between the two enzymes concern the shape and electrostatics of a large (450 Angstrom(3)) cavity at the dimer interface. This cavity binds numerous noncompetitive inhibitors and is a target for selective drug design. A 34-residue insertion specific for the GRs of malarial parasites shows no density, implying that it is disordered. The precise location of this insertion along the sequence allows us to explain the deleterious effects of a mutant in this region and suggests new functional studies. To complement the structural comparisons, we report the relative susceptibility of human and plasmodial GRs to a series of tricyclic inhibitors as well as to peptides designed to interfere with protein folding and dimerization. Enzyme-kinetic studies on GRs from chloroquine-resistant and chloroquine-sensitive parasite strains were performed and indicate that the structure reported here represents GR of P. falciparum strains in general and thus is a highly relevant target for drug development. (C) 2003 Elsevier Science Ltd. All rights reserved.

Harvard Citation style: Sarma, G., Savvides, S., Becker, K., Schirmer, M., Schirmer, R. and Karplus, P. (2003) Glutathione reductase of the malarial parasite Plasmodium falciparum: Crystal structure and inhibitor development, Journal of Molecular Biology, 328(4), pp. 893-907. https://doi.org/10.1016/S0022-2836(03)00347-4

APA Citation style: Sarma, G., Savvides, S., Becker, K., Schirmer, M., Schirmer, R., & Karplus, P. (2003). Glutathione reductase of the malarial parasite Plasmodium falciparum: Crystal structure and inhibitor development. Journal of Molecular Biology. 328(4), 893-907. https://doi.org/10.1016/S0022-2836(03)00347-4