1ONF

Crystal structure of Plasmodium falciparum Glutathione reductase

1ONF の概要

• エントリーDOI: 10.2210/pdb1onf/pdb
• 分子名称: Glutathione reductase, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• 機能のキーワード: oxidoreductase
• 由来する生物種: Plasmodium falciparum (malaria parasite P. falciparum)
• 細胞内の位置: Cytoplasm: Q94655
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 57424.53

構造登録者

Sarma, G.N.,Savvides, S.N.,Becker, K.,Schirmer, M.,Schirmer, R.H.,Karplus, P.A. (登録日: 2003-02-27, 公開日: 2003-05-06, 最終更新日: 2024-11-20)

主引用文献

Sarma, G.N.,Savvides, S.N.,Becker, K.,Schirmer, M.,Schirmer, R.H.,Karplus, P.A.
Glutathione reductase of the malarial parasite Plasmodium falciparum: Crystal structure and inhibitor development
J.Mol.Biol., 328:893-907, 2003

PubMed 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(+) <==> NADP(+)+2 GSH) has become an attractive drug target for antimalarial drug development. Here, we report the 2.6A 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 (450A(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.

PubMed: 12729762
DOI: 10.1016/S0022-2836(03)00347-4

実験手法

X-RAY DIFFRACTION (2.6 Å)