Controlling Allosteric Networks in Proteins

Chem Rev. 2016 Jun 8;116(11):6463-87. doi: 10.1021/acs.chemrev.5b00544. Epub 2016 Feb 19.

Abstract

Allosteric transition, defined as conformational changes induced by ligand binding, is one of the fundamental properties of proteins. Allostery has been observed and characterized in many proteins, and has been recently utilized to control protein function via regulation of protein activity. Here, we review the physical and evolutionary origin of protein allostery, as well as its importance to protein regulation, drug discovery, and biological processes in living systems. We describe recently developed approaches to identify allosteric pathways, connected sets of pairwise interactions that are responsible for propagation of conformational change from the ligand-binding site to a distal functional site. We then present experimental and computational protein engineering approaches for control of protein function by modulation of allosteric sites. As an example of application of these approaches, we describe a synergistic computational and experimental approach to rescue the cystic-fibrosis-associated protein cystic fibrosis transmembrane conductance regulator, which upon deletion of a single residue misfolds and causes disease. This example demonstrates the power of allosteric manipulation in proteins to both elucidate mechanisms of molecular function and to develop therapeutic strategies that rescue those functions. Allosteric control of proteins provides a tool to shine a light on the complex cascades of cellular processes and facilitate unprecedented interrogation of biological systems.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Focal Adhesion Protein-Tyrosine Kinases / chemistry
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Humans
  • Ligands
  • Molecular Dynamics Simulation
  • Protein Structure, Quaternary
  • Proteins / chemistry
  • Proteins / metabolism*

Substances

  • Ligands
  • Proteins
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Focal Adhesion Protein-Tyrosine Kinases