Ligand chirality effects on the dynamics of human 3-phosphoglycerate kinase: Comparison between D- and L-nucleotides

Zoltan Palmai, David Perahia, Corinne Lionne, Judit Fidy, Erika Balog, Laurent Chaloin

Research output: Contribution to journalArticle

2 Citations (Scopus)


l-nucleoside analogues are now largely used as antiviral drugs for the treatment of viral infections like HBV, HCV and HIV. However, in order to be fully active, they need to be phosphorylated by cellular or viral kinases. Human 3-phosphogycerate kinase (hPGK) was shown to catalyze the last step of activation of l-enantiomers and thus constitutes an attractive target for theoretical predictions of its phosphorylation efficiency. Molecular dynamics simulations were carried out with four different nucleotides (d-/l-ADP and d-/l-CDP) in complex with hPGK and 1,3-bisphospho-d-glycerate (bPG). The binding affinities of CDPs (both enantiomers) for hPGK were found very weak while d- and l-ADP were better substrates. Interestingly, the binding affinity of the bPG substrate was found to be lower in presence of d-ADP than l-ADP which indicates a potential antagonistic effect on one substrate to the other. A detailed analysis of the simulations unravels important dynamic conditions for efficient phosphorylation. Indeed, as previously described for the natural substrate, the hinge bending motion of the domains upon substrates binding should be more correlated and directional. Interestingly, the unforeseen finding was the larger dynamics freedoms observed for the substrates that was favored by the protein atoms flexibility around the nucleobase binding site.

Original languageEnglish
Pages (from-to)88-100
Number of pages13
JournalArchives of Biochemistry and Biophysics
Issue number1-2
Publication statusPublished - Jul 2011


  • Antiviral analogues
  • Hinge bending
  • Human PGK
  • Molecular dynamics
  • l-Enantiomers

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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