 |
PDBsum entry 1cet
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
1cet
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Chloroquine binds in the cofactor binding site of plasmodium falciparum lactate dehydrogenase.
|
|
|
Authors
|
|
J.A.Read,
K.W.Wilkinson,
R.Tranter,
R.B.Sessions,
R.L.Brady.
|
|
|
Ref.
|
|
J Biol Chem, 1999,
274,
10213-10218.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
|
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.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
The structure of lactate dehydrogenase from plasmodium falciparum reveals a new target for anti-Malarial design.
|
|
|
Authors
|
|
C.R.Dunn,
M.J.Banfield,
J.J.Barker,
C.W.Higham,
K.M.Moreton,
D.Turgut-Balik,
R.L.Brady,
J.J.Holbrook.
|
|
|
Ref.
|
|
Nat Struct Biol, 1996,
3,
912-915.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
