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PDBsum entry 1cet

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Oxidoreductase PDB id
1cet
Jmol
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    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q27743  (LDH_PLAFD) -  L-lactate dehydrogenase
Seq:
Struc:
316 a.a.
305 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.1.1.1.27  - L-lactate dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (S)-lactate + NAD+ = pyruvate + NADH
(S)-lactate
+ NAD(+)
= pyruvate
+ NADH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   4 terms 
  Biochemical function     catalytic activity     4 terms  

 

 
    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.  

Literature references that cite this PDB file's key reference Google scholar

  PubMed id Reference
17461976 V.Wiwanitkit (2007).
Plasmodium and host lactate dehydrogenase molecular function and biological pathways: implication for antimalarial drug discovery.
  Chem Biol Drug Des, 69, 280-283.  
16688469 G.Lu, X.Hu, Z.Peng, H.Xie, Y.Li, Z.Wu, and X.Yu (2006).
Expression and characterization of lactate dehydrogenase from Schistosoma japonicum.
  Parasitol Res, 99, 593-596.  
10468562 X.G.Gao, E.Maldonado, R.Pérez-Montfort, G.Garza-Ramos, M.T.de Gómez-Puyou, A.Gómez-Puyou, and A.Rodríguez-Romero (1999).
Crystal structure of triosephosphate isomerase from Trypanosoma cruzi in hexane.
  Proc Natl Acad Sci U S A, 96, 10062-10067.
PDB code: 1ci1
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