Allosteric inhibition through suppression of transient conformational states

Nat Chem Biol. 2013 Jul;9(7):462-5. doi: 10.1038/nchembio.1250. Epub 2013 May 5.


The ability to inhibit binding or enzymatic activity is key to preventing aberrant behaviors of proteins. Allosteric inhibition is desirable as it offers several advantages over competitive inhibition, but the mechanisms of action remain poorly understood in most cases. Here we show that allosteric inhibition can be effected by destabilizing a low-populated conformational state that serves as an on-pathway intermediate for ligand binding, without altering the protein's ground-state structure. As standard structural approaches are typically concerned with changes in the ground-state structure of proteins, the presence of such a mechanism can go easily undetected. Our data strongly argue for the routine use of NMR tools suited to detect and characterize transiently formed conformational states in allosteric systems. Structure information on such important intermediates can ultimately result in more efficient design of allosteric inhibitors.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allosteric Site*
  • Calorimetry / methods
  • Cyclic AMP Receptor Protein / chemistry*
  • Cyclic AMP Receptor Protein / metabolism
  • DNA / chemistry
  • Escherichia coli / metabolism*
  • Ligands
  • Magnetic Resonance Spectroscopy / methods*
  • Models, Molecular
  • Mutation
  • Protein Binding
  • Protein Conformation


  • Cyclic AMP Receptor Protein
  • Ligands
  • DNA

Associated data

  • PDB/4BH9
  • PDB/4BHP