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PDBsum entry 1u4o

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Oxidoreductase PDB id
1u4o
Jmol
Contents
Protein chain
309 a.a. *
Ligands
NDD
MPD ×2
Waters ×319
* Residue conservation analysis
PDB id:
1u4o
Name: Oxidoreductase
Title: Plasmodium falciparum lactate dehydrogenase complexed with 2 naphthalenedicarboxylic acid
Structure: L-lactate dehydrogenase. Chain: a. Synonym: ldh-p. 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:
1.70Å     R-factor:   0.147     R-free:   0.181
Authors: R.Conners,A.Cameron,J.Read,F.Schambach,R.B.Sessions,R.L.Brad
Key ref: R.Conners et al. (2005). Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase. Mol Biochem Parasitol, 142, 137-148. PubMed id: 15978953 DOI: 10.1016/j.molbiopara.2005.03.015
Date:
26-Jul-04     Release date:   21-Jun-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q27743  (LDH_PLAFD) -  L-lactate dehydrogenase
Seq:
Struc:
316 a.a.
309 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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
Bound ligand (Het Group name = MPD)
matches with 40.00% similarity
+ 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: 10.1016/j.molbiopara.2005.03.015 Mol Biochem Parasitol 142:137-148 (2005)
PubMed id: 15978953  
 
 
Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase.
R.Conners, F.Schambach, J.Read, A.Cameron, R.B.Sessions, L.Vivas, A.Easton, S.L.Croft, R.L.Brady.
 
  ABSTRACT  
 
Gossypol is a di-sesquiterpene natural-product in the form of a functionalised binaphthyl and is isolated from cotton plants. The compound has long been known to exhibit anti-malarial and other biological activities. Previous studies have indicated that compounds of this type target Plasmodium falciparum lactate dehydrogenase (pfLDH), an essential enzyme for energy generation within the parasite. In this study, we report that simple naphthalene-based compounds, the core of the gossypol structure, exhibit weak inhibition of the parasite lactate dehydrogenase. Crystal structures of the complexes formed by binding of these naphthalene-based compounds to their target enzyme have been used to delineate the molecular features likely to form the gossypol binding site. Two modes of binding are observed: one overlapping the pyruvate but not the co-factor site, the other bridging the binding sites for the co-factor nicontinamide group and pyruvate substrate. This latter site encompasses molecular features unique to Plasmodium forms of LDH and is likely to represent the mode of binding for gossypol derivatives that show selectivity for the parasite enzymes. We also report a substrate analogue that unexpectedly binds within the adenine pocket of the co-factor groove. Although these core pharmacophore-like molecules only exhibit low levels of inhibitory activity, these molecular snapshots provide a rational basis for renewed structure-based development of naphthalene-based compounds as anti-malarial agents.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
17597109 C.H.Ko, S.C.Shen, L.Y.Yang, C.W.Lin, and Y.C.Chen (2007).
Gossypol reduction of tumor growth through ROS-dependent mitochondria pathway in human colorectal carcinoma cells.
  Int J Cancer, 121, 1670-1679.  
17459101 D.K.Shoemark, M.J.Cliff, R.B.Sessions, and A.R.Clarke (2007).
Enzymatic properties of the lactate dehydrogenase enzyme from Plasmodium falciparum.
  FEBS J, 274, 2738-2748.  
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.  
16538663 P.Przybylski, G.Bejcar, A.HuczyƄski, G.Schroeder, B.Brzezinski, and F.Bartl (2006).
1H- and 13C-NMR, FTIR, UV-VIS, ESI-MS, and PM5 studies as well as emission properties of a new Schiff base of gossypol with 5-methoxytryptamine and a new hydrazone of gossypol with dansylhydrazine.
  Biopolymers, 82, 521-535.  
16255680 K.Dodou, R.J.Anderson, D.A.Small, and P.W.Groundwater (2005).
Investigations on gossypol: past and present developments.
  Expert Opin Investig Drugs, 14, 1419-1434.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.