Asparagine deamidation at the NGR sequence in the 5th type I repeat of fibronectin (FN-I5) generates isoDGR, an avß3 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 to NGR, RGD or DGR-containing cyclo-peptides. Docking experiments show that isoDGR, exploiting an inverted orientation as compared to RGD, favorably interacts with the RGD-binding site of avß3, both recapitulating canonical RGD/avß3 contacts and establishing additional polar interactions. Conversely, NGR and DGR motives 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 avß3. These findings contribute to explain the different functional properties of FN-I5 before and after deamidation, and provide support for the hypothesis that NGRisoDGR transition can work as a molecular timer for activating latent integrin-binding sites in proteins, thus regulating protein function.