PDBsum entry 1cet

Oxidoreductase

PDB id: 1cet

Contents

Protein chain

305 a.a. *

Ligands

CLQ

Waters ×252

* Residue conservation analysis

PDB id:

1cet

Name:

Oxidoreductase

Title:

Chloroquine binds in the cofactor binding site of plasmodium falciparum lactate dehydrogenase.

Structure:

Protein (l-lactate dehydrogenase). Chain: a. Engineered: yes

Source:

Plasmodium falciparum. Malaria parasite p. Falciparum. Organism_taxid: 5833. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Tetramer (from PDB file)

Resolution:

2.05Å R-factor: 0.154 R-free: 0.193

Authors:

J.A.Read,K.W.Wilkinson,R.Tranter,R.B.Sessions,R.L.Brady

Key ref:

J.A.Read et al. (1999). Chloroquine binds in the cofactor binding site of Plasmodium falciparum lactate dehydrogenase. J Biol Chem, 274, 10213-10218. PubMed id: 10187806 DOI: 10.1074/jbc.274.15.10213

Date:

10-Mar-99 Release date: 19-Mar-99

Protein chain

Q27743  (LDH_PLAFD) -  L-lactate dehydrogenase from Plasmodium falciparum (isolate CDC / Honduras)

Seq: 316 a.a.

Struc: 305 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.1.1.1.27 - L-lactate dehydrogenase.
• Reaction: (S)-lactate + NAD⁺ = pyruvate + NADH + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1074/jbc.274.15.10213

J Biol Chem 274:10213-10218 (1999)

PubMed id: 10187806

Chloroquine binds in the cofactor binding site of Plasmodium falciparum lactate dehydrogenase.

J.A.Read, K.W.Wilkinson, R.Tranter, R.B.Sessions, R.L.Brady.

ABSTRACT

Although the molecular mechanism by which chloroquine exerts its effects on the malarial parasite Plasmodium falciparum remains unclear, the drug has previously been found to interact specifically with the glycolytic enzyme lactate dehydrogenase from the parasite. In this study we have determined the crystal structure of the complex between chloroquine and P. falciparum lactate dehydrogenase. The bound chloroquine is clearly seen within the NADH binding pocket of the enzyme, occupying a position similar to that of the adenyl ring of the cofactor. Chloroquine hence competes with NADH for binding to the enzyme, acting as a competitive inhibitor for this critical glycolytic enzyme. Specific interactions between the drug and amino acids unique to the malarial form of the enzyme suggest this binding is selective. Inhibition studies confirm that chloroquine acts as a weak inhibitor of lactate dehydrogenase, with mild selectivity for the parasite enzyme. As chloroquine has been shown to accumulate to millimolar concentrations within the food vacuole in the gut of the parasite, even low levels of inhibition may contribute to the biological efficacy of the drug. The structure of this enzyme-inhibitor complex provides a template from which the quinoline moiety might be modified to develop more efficient inhibitors of the enzyme.

Selected figure(s)

Figure 1.
Fig. 1. Molecular structures of (left) chloroquine and (right) hematin.

Figure 5.
Fig. 5. Stereo view of a superimposition of the chloroquine complex onto the coordinates of ternary pfLDH (PDB code 1ldg.pdb, Ref. 1) showing that the quinoline ring occupies a position similar to that of the adenyl ring of NADH. Protein residues within 3.5 Å of the NADH from the ternary complex are shown in green and those within 4.5 Å of chloroquine from the CQ-pfLDH complex are shown in red. The chlorine atom of chloroquine is depicted as a red sphere.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (1999, 274, 10213-10218) copyright 1999.

Figures were selected by the author.