Small-molecule displacement of a cryptic degron causes conditional protein degradation

Nat Chem Biol. 2011 Jul 3;7(8):531-7. doi: 10.1038/nchembio.598.


The ability to rapidly regulate the functions of specific proteins in living cells is a valuable tool for biological research. Here we describe a new technique by which the degradation of a specific protein is induced by a small molecule. A protein of interest is fused to a ligand-induced degradation (LID) domain, resulting in the expression of a stable and functional fusion protein. The LID domain is comprised of the FK506- and rapamycin-binding protein (FKBP) and a 19-amino-acid degron fused to the C terminus of FKBP. In the absence of the small molecule Shield-1, the degron is bound to the FKBP fusion protein and the protein is stable. When present, Shield-1 binds tightly to FKBP, displacing the degron and inducing rapid and processive degradation of the LID domain and any fused partner protein. Structure-function studies of the 19-residue peptide showed that a 4-amino-acid sequence within the peptide is responsible for degradation.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bacterial Proteins
  • Catalytic Domain
  • Cell Line
  • Cloning, Molecular
  • Gene Expression Regulation / physiology
  • Luminescent Proteins
  • Mice
  • Models, Molecular
  • Morpholines / pharmacology
  • Peptides / metabolism
  • Protein Denaturation*
  • Protein Structure, Tertiary
  • Tacrolimus Binding Proteins / chemistry*
  • Tacrolimus Binding Proteins / genetics
  • Tacrolimus Binding Proteins / metabolism


  • Bacterial Proteins
  • Luminescent Proteins
  • Morpholines
  • Peptides
  • Shield-1 compound
  • yellow fluorescent protein, Bacteria
  • Tacrolimus Binding Proteins

Associated data

  • PubChem-Substance/123101663
  • PubChem-Substance/123101664