Unnatural amino acids as probes of ligand-receptor interactions and their conformational consequences

Annu Rev Pharmacol Toxicol. 2013;53:211-29. doi: 10.1146/annurev-pharmtox-011112-140343.


G protein-coupled receptors and ion channels couple a wide range of external stimuli to cellular growth and division, metabolism, motility, and a myriad of intra- and intercellular signaling pathways. G protein-coupled receptors initiate complex, interrelated downstream signaling cascades, whereas rapid ionic flux through channels directly supports membrane excitability and mediates cellular functions through second messengers. Because of these characteristics, these ubiquitous transmembrane proteins are valuable therapeutic targets and have provided fertile ground for the development of leading-edge synthetic and chemical biological approaches. Here we summarize recent advances in the use of site-directed incorporation of unnatural amino acids and chemical probes to study ligand-receptor interactions, determine the location of binding sites, and examine the downstream conformational consequences of ligand binding in G protein-coupled receptors and ion channels.

Publication types

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

MeSH terms

  • Amino Acids / chemistry
  • Amino Acids / metabolism*
  • Animals
  • Binding Sites
  • Humans
  • Ion Channels / chemistry
  • Ion Channels / metabolism*
  • Ligands
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Protein Conformation
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*
  • Structure-Activity Relationship


  • Amino Acids
  • Ion Channels
  • Ligands
  • Membrane Proteins
  • Receptors, G-Protein-Coupled