Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor

Cell. 1996 May 31;85(5):695-705. doi: 10.1016/s0092-8674(00)81236-2.


Crystal structures of the insulin receptor substrate-1 (IRS-1) phosphotyrosine-binding (PTB) domain, alone and complexed with the juxtamembrane region of the insulin receptor, show how this domain recognizes phosphorylated "NPXY" sequence motifs. The domain is a 7-stranded beta sandwich capped by a C-terminal helix. The insulin receptor phosphopeptide fills an L-shaped cleft on the domain. The N-terminal residues of the bound peptide form an additional strand in the beta sandwich, stabilized by contacts with the C-terminal helix. These interactions explain why IRS-1 binds to the insulin receptor but not to NPXpY motifs in growth factor receptors. The PTB domains of IRS-1 and Shc share a common fold with pleckstrin homology domains. Overall, ligand binding by IRS-1 and Shc PTB domains is similar, but residues critical for phosphotyrosine recognition are not conserved.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Insulin Receptor Substrate Proteins
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Peptide Mapping
  • Phosphoproteins / chemistry*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphotyrosine / metabolism
  • Protein Conformation
  • Receptor, Insulin / chemistry*
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism*
  • src Homology Domains


  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins
  • Phosphotyrosine
  • Receptor, Insulin