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PDBsum entry 4i8x

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protein ligands Protein-protein interface(s) links
Oxidoreductase/oxidoreductase inhibitor PDB id
4i8x
Jmol
Contents
Protein chains
(+ 2 more) 321 a.a.
Ligands
6P3 ×8
Waters ×425
PDB id:
4i8x
Name: Oxidoreductase/oxidoreductase inhibitor
Title: Crystal structure of rabbit ldha in complex with ap27460
Structure: L-lactate dehydrogenase a chain. Chain: a, b, c, d, e, f, g, h. Synonym: lactate dehydrogenase a, ldha, ldh-a, ldh muscle s ldh-m. Ec: 1.1.1.27
Source: Oryctolagus cuniculus. Rabbit. Organism_taxid: 9986
Resolution:
2.23Å     R-factor:   0.201     R-free:   0.236
Authors: T.Zhou,Z.G.Stephan,A.Kohlmann,F.Li,L.Commodore,M.T.Greenfiel D.C.Dalgarno
Key ref: A.Kohlmann et al. (2013). Fragment growing and linking lead to novel nanomolar lactate dehydrogenase inhibitors. J Med Chem, 56, 1023-1040. PubMed id: 23302067 DOI: 10.1021/jm3014844
Date:
04-Dec-12     Release date:   23-Jan-13    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P13491  (LDHA_RABIT) -  L-lactate dehydrogenase A chain
Seq:
Struc:
332 a.a.
321 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
+ NAD(+)
= pyruvate
+ NADH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     oxidation-reduction process   4 terms 
  Biochemical function     catalytic activity     4 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm3014844 J Med Chem 56:1023-1040 (2013)
PubMed id: 23302067  
 
 
Fragment growing and linking lead to novel nanomolar lactate dehydrogenase inhibitors.
A.Kohlmann, S.G.Zech, F.Li, T.Zhou, R.M.Squillace, L.Commodore, M.T.Greenfield, X.Lu, D.P.Miller, W.S.Huang, J.Qi, R.M.Thomas, Y.Wang, S.Zhang, R.Dodd, S.Liu, R.Xu, Y.Xu, J.J.Miret, V.Rivera, T.Clackson, W.C.Shakespeare, X.Zhu, D.C.Dalgarno.
 
  ABSTRACT  
 
Lactate dehydrogenase A (LDH-A) catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway. Cancer cells rely heavily on glycolysis instead of oxidative phosphorylation to generate ATP, a phenomenon known as the Warburg effect. The inhibition of LDH-A by small molecules is therefore of interest for potential cancer treatments. We describe the identification and optimization of LDH-A inhibitors by fragment-based drug discovery. We applied ligand based NMR screening to identify low affinity fragments binding to LDH-A. The dissociation constants (K(d)) and enzyme inhibition (IC(50)) of fragment hits were measured by surface plasmon resonance (SPR) and enzyme assays, respectively. The binding modes of selected fragments were investigated by X-ray crystallography. Fragment growing and linking, followed by chemical optimization, resulted in nanomolar LDH-A inhibitors that demonstrated stoichiometric binding to LDH-A. Selected molecules inhibited lactate production in cells, suggesting target-specific inhibition in cancer cell lines.