PDBsum entry: 2bma

Oxidoreductase

PDB id: 2bma

Contents

Protein chains

(+ 0 more) 467 a.a. *

* Residue conservation analysis

PDB id:

2bma

Name:

Oxidoreductase

Title:

The crystal structure of plasmodium falciparum glutamate dehydrogenase, a putative target for novel antimalarial drugs

Structure:

Glutamate dehydrogenase (NADP+). Chain: a, b, c, d, e, f. Engineered: yes

Source:

Plasmodium falciparum. Organism_taxid: 5833. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Hexamer (from PDB file)

Resolution:

2.7Å R-factor: 0.248 R-free: 0.276

Authors:

C.Werner,M.T.Stubbs,R.L.Krauth-Siege,G.Klebe

Key ref:

C.Werner et al. (2005). The crystal structure of Plasmodium falciparum glutamate dehydrogenase, a putative target for novel antimalarial drugs. J Mol Biol, 349, 597-607. PubMed id: 15878595 DOI: 10.1016/j.jmb.2005.03.077

Date:

10-Mar-05 Release date: 19-May-05

Protein chains

O96940  (O96940_PLAFA) -  Glutamate dehydrogenase

Seq: 470 a.a.

Struc: 467 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 

• Biological process: oxidation-reduction process (2 terms)
• Biochemical function: nucleotide binding (3 terms)

DOI no: 10.1016/j.jmb.2005.03.077

J Mol Biol 349:597-607 (2005)

PubMed id: 15878595

The crystal structure of Plasmodium falciparum glutamate dehydrogenase, a putative target for novel antimalarial drugs.

C.Werner, M.T.Stubbs, R.L.Krauth-Siegel, G.Klebe.

ABSTRACT

Plasmodium falciparum is the main causative agent of tropical malaria, the most severe parasitic disease in the world. Growing resistance of Plasmodia towards available drugs is an increasing problem in countries where malaria is endemic. As Plasmodia are sensitive to oxidative stress, augmenting this in the parasite represents a promising principle for the development of novel antimalarial drugs. The NADP-dependent glutamate dehydrogenase (GDH) of P.falciparum is largely responsible for the production of NADPH in the parasite, which in turn serves as electron source for the antioxidative enzymes glutathione reductase and thioredoxin reductase. As GDH does not occur in the host erythrocyte, GDH is a particularly attractive target for drug therapy. The three-dimensional structure of P.falciparum GDH in the unligated state has been determined by X-ray crystallography to a resolution of 2.7A. Compared to the mammalian enzymes, two amino acid residues are exchanged in the putative active site of the parasite GDH. The most obvious differences between parasite and human GDH are the subunit interfaces of the hexameric proteins. In the parasite protein, several salt-bridges mediate contacts between the subunits whereas in the human enzyme these interactions are mainly of hydrophobic nature. Furthermore, P.falciparum GDH possesses a unique N-terminal extension that does not occur in any other GDH sequence so far studied. These findings might be exploited for the design of peptidomimetics capable of disrupting the oligomeric organisation of the parasite enzyme.

Selected figure(s)

Figure 2.
Figure 2. Stereo views of the P. falciparum GDH hexamer along (a) the 2-fold and (b) the 3-fold axes. The individual monomers are coloured as follows: A, dark blue; B, light green; C, green; D, light yellow; E, light blue; and F, yellow. The locations of the active sites are indicated by the red surface. The A monomer is chosen as reference.

Figure 6.
Figure 6. Two examples for the charge-assisted network of hydrogen bonds in the subunit-subunit interface of P. falciparum GDH.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 349, 597-607) copyright 2005.

Figures were selected by an automated process.