Modulation of allostery of pyruvate kinase by shifting of an ensemble of microstates

J. Ching Lee

Research output: Contribution to journalReview articlepeer-review

12 Scopus citations


Since the introduction of the concepts of allostery about four decades ago, much advancement has been made in elucidating the structure-function correlation in allostery. However, there are still a number of issues that remain unresolved. In this review we used mammalian pyruvate kinase (PK) as a model system to understand the role of protein dynamics in modulating cooperativity. PK has a triosephosphate isomerase (TIM)(α/β) 8 barrel structural motif. PK is an ideal system to address basic questions regarding regulatory mechanisms about this common (α/β) 8 structural motif. The simplest model accounting for all of the solution thermodynamic and kinetic data on ligand-enzyme interactions involves two conformational states, inactive ET and active ER. These conformational states are represented by domain movements. Further studies provide the first evidence for a differential effect of ligand binding on the dynamics of the structural elements, not major secondary structural changes. These data are consistent with our model that allosteric regulation of PK is the consequence of perturbation of the distribution of an ensemble of states in which the inactive ET and active ER represent the two extreme end states. Sequence differences and ligands can modulate the distribution of states leading to alterations of functions. The future work includes: defining the network of functionally connected residues; elucidating the chemical principles governing the sequence differences which affect functions; and probing the nature of mutations on the stability of the secondary structural elements, which in turn modulate allostery.

Original languageEnglish (US)
Pages (from-to)663-669
Number of pages7
JournalActa Biochimica et Biophysica Sinica
Issue number7
StatePublished - Jul 2008
Externally publishedYes


  • Allostery
  • Human genetics
  • Protein dynamics
  • Protein fold
  • Thermodynamics

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Biochemistry


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