An Allosteric Signaling Pathway of Human 3-Phosphoglycerate Kinase from Force Distribution Analysis

Zoltan Palmai, Christian Seifert, Frauke Gräter, E. Balog

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

3-Phosphogycerate kinase (PGK) is a two domain enzyme, which transfers a phosphate group between its two substrates, 1,3-bisphosphoglycerate bound to the N-domain and ADP bound to the C-domain. Indispensable for the phosphoryl transfer reaction is a large conformational change from an inactive open to an active closed conformation via a hinge motion that should bring substrates into close proximity. The allosteric pathway resulting in the active closed conformation has only been partially uncovered. Using Molecular Dynamics simulations combined with Force Distribution Analysis (FDA), we describe an allosteric pathway, which connects the substrate binding sites to the interdomain hinge region. Glu192 of alpha-helix 7 and Gly394 of loop L14 act as hinge points, at which these two secondary structure elements straighten, thereby moving the substrate-binding domains towards each other. The long-range allosteric pathway regulating hPGK catalytic activity, which is partially validated and can be further tested by mutagenesis, highlights the virtue of monitoring internal forces to reveal signal propagation, even if only minor conformational distortions, such as helix bending, initiate the large functional rearrangement of the macromolecule.

Original languageEnglish
Article numbere1003444
JournalPLoS Computational Biology
Volume10
Issue number1
DOIs
Publication statusPublished - Jan 2014

Fingerprint

phosphoglycerate kinase
Phosphoglycerate Kinase
Signaling Pathways
Molecular Dynamics Simulation
Mutagenesis
Adenosine Diphosphate
Phosphotransferases
Hinges
Phosphates
Binding Sites
Substrate
substrate
Pathway
molecular dynamics
Substrates
Enzymes
Helix
Conformation
catalytic activity
mutagenesis

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Ecology
  • Molecular Biology
  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Modelling and Simulation
  • Computational Theory and Mathematics

Cite this

An Allosteric Signaling Pathway of Human 3-Phosphoglycerate Kinase from Force Distribution Analysis. / Palmai, Zoltan; Seifert, Christian; Gräter, Frauke; Balog, E.

In: PLoS Computational Biology, Vol. 10, No. 1, e1003444, 01.2014.

Research output: Contribution to journalArticle

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