Structural basis for the interaction of isoDGR with the RGD-binding site of alphavbeta3 integrin

J Biol Chem. 2008 Jul 11;283(28):19757-68. doi: 10.1074/jbc.M710273200. Epub 2008 May 13.


Asparagine deamidation at the NGR sequence in the 5th type I repeat of fibronectin (FN-I5) generates isoDGR, an alphavbeta3 integrin-binding motif regulating endothelial cell adhesion and proliferation. By NMR and molecular dynamics studies, we analyzed the structure of CisoDGRC (isoDGR-2C), a cyclic beta-peptide mimicking the FN-I5 site, and compared it with NGR, RGD, or DGR-containing cyclopeptides. Docking experiments show that isoDGR, exploiting an inverted orientation as compared with RGD, favorably interacts with the RGD-binding site of alphavbeta3, both recapitulating canonical RGD-alphavbeta3 contacts and establishing additional polar interactions. Conversely, NGR and DGR motifs lack the fundamental pharmacophoric requirements for high receptor affinity. Therefore, unlike NGR and DGR, isoDGR is a new natural recognition motif of the RGD-binding pocket of alphavbeta3. These findings contribute to explain the different functional properties of FN-I5 before and after deamidation, and provide support for the hypothesis that NGR --> isoDGR transition can work as a molecular timer for activating latent integrin-binding sites in proteins, thus regulating protein function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / physiology
  • Binding Sites / physiology
  • Cell Line, Tumor
  • Deamination
  • Fibronectins / chemistry
  • Fibronectins / metabolism
  • Humans
  • Integrin alphaVbeta3 / chemistry*
  • Integrin alphaVbeta3 / metabolism
  • Nuclear Magnetic Resonance, Biomolecular / methods
  • Oligopeptides / chemistry*
  • Oligopeptides / metabolism
  • Protein Binding / physiology


  • Fibronectins
  • Integrin alphaVbeta3
  • NGR peptide
  • Oligopeptides