Glutathione Reductase of the Malarial Parasite Plasmodium falciparum: Crystal Structure and Inhibitor Development

The malarial parasite Plasmodium falciparum is known to be sensitive to oxidative stress, and thus the antioxidant enzyme glutathione reductase (GR; NADPH+GSSG+H +⇄NADP ++2 GSH) has become an attractive drug target for antimalarial drug development. Here, we report the 2.6 Å resolution crystal struc...

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Bibliographic Details
Published in:	Journal of molecular biology Vol. 328; no. 4; pp. 893 - 907
Main Authors:	Sarma, G.N., Savvides, S.N., Becker, K., Schirmer, M., Schirmer, R.H., Karplus, P.A.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 09-05-2003
Subjects:	10-arylisoalloxazines Amino Acid Sequence Animals Binding Sites crystal structure Crystallography, X-Ray Dimerization Drug Design Enzyme Inhibitors - pharmacology Flavins - pharmacology glutathione reductase Glutathione Reductase - antagonists & inhibitors Glutathione Reductase - chemistry Humans malaria Models, Chemical Models, Molecular Molecular Sequence Data Peptides - chemistry Plasmodium falciparum Plasmodium falciparum - enzymology Plasmodium falciparum glutathione reductase Protein Conformation Recombinant Proteins - chemistry Sequence Homology, Amino Acid GSSG, oxidized glutathione TLS, translation, libration and screw-rotation drug design EcGR, Escherichia coli glutathione reductase crystal structure 10-arylisoalloxazines Plasmodium falciparum glutathione reductase malaria PfGR, Plasmodium falciparum glutathione reductase arilloxazines, 10-arylisoalloxazines ρ rms, root-mean-square electron density of map, often reported as σ hGR, human glutathione reductase
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Summary:	The malarial parasite Plasmodium falciparum is known to be sensitive to oxidative stress, and thus the antioxidant enzyme glutathione reductase (GR; NADPH+GSSG+H +⇄NADP ++2 GSH) has become an attractive drug target for antimalarial drug development. Here, we report the 2.6 Å 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 Å 3) cavity at the dimer interface. This cavity binds numerous non-competitive 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-2836 1089-8638
DOI:	10.1016/S0022-2836(03)00347-4