Unnatural ligands for engineered proteins: new tools for chemical genetics

Annu Rev Biophys Biomol Struct. 2000;29:577-606. doi: 10.1146/annurev.biophys.29.1.577.


Small molecules that modulate the activity of biological signaling molecules can be powerful probes of signal transduction pathways. Highly specific molecules with high affinity are difficult to identify because of the conserved nature of many protein active sites. A newly developed approach to discovery of such small molecules that relies on protein engineering and chemical synthesis has yielded powerful tools for the study of a wide variety of proteins involved in signal transduction (G-proteins, protein kinases, 7-transmembrane receptors, nuclear hormone receptors, and others). Such chemical genetic tools combine the advantages of traditional genetics and the unparalleled temporal control over protein function afforded by small molecule inhibitors/activators that act at diffusion controlled rates with targets.

Publication types

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

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • GTP Phosphohydrolases / chemistry
  • Genetic Techniques*
  • Humans
  • Kinesin / chemistry
  • Kinesin / genetics
  • Ligands*
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Myosins / chemistry
  • Myosins / genetics
  • Protein Engineering*
  • Protein Kinases / chemistry
  • Proteins / chemical synthesis
  • Signal Transduction


  • Ligands
  • Proteins
  • Protein Kinases
  • GTP Phosphohydrolases
  • Myosins
  • Kinesin