1CET
CHLOROQUINE BINDS IN THE COFACTOR BINDING SITE OF PLASMODIUM FALCIPARUM LACTATE DEHYDROGENASE.
Summary for 1CET
| Entry DOI | 10.2210/pdb1cet/pdb |
| Descriptor | PROTEIN (L-LACTATE DEHYDROGENASE), N4-(7-CHLORO-QUINOLIN-4-YL)-N1,N1-DIETHYL-PENTANE-1,4-DIAMINE (3 entities in total) |
| Functional Keywords | oxidoreductase, tricarboxylic acid cycle, inhibitor |
| Biological source | Plasmodium falciparum (malaria parasite P. falciparum) |
| Total number of polymer chains | 1 |
| Total formula weight | 34482.66 |
| Authors | Read, J.A.,Wilkinson, K.W.,Tranter, R.,Sessions, R.B.,Brady, R.L. (deposition date: 1999-03-10, release date: 1999-03-19, Last modification date: 2023-08-09) |
| Primary citation | Read, J.A.,Wilkinson, K.W.,Tranter, R.,Sessions, R.B.,Brady, R.L. Chloroquine binds in the cofactor binding site of Plasmodium falciparum lactate dehydrogenase. J.Biol.Chem., 274:10213-10218, 1999 Cited by PubMed 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. PubMed: 10187806DOI: 10.1074/jbc.274.15.10213 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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