Data di Pubblicazione:
2008
Citazione:
Structural basis for the interaction of isoDGR with the RGD-binding site of αvβ3 integrin / A. Spitaleri, S. Mari, F. Curnis, C. Traversari, R. Longhi, C. Bordignon, A. Corti, G.-. Rizzardi, G. Musco. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 283:28(2008), pp. 19757-19768. [10.1074/jbc.M710273200]
Abstract:
Asparagine deamidation at the NGR sequence in the 5th type I repeat of fibronectin (FN-I5) generates isoDGR, an αvβ3 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 β-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 αvβ3, both recapitulating canonical RGD-αvβ3 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 αvβ3. 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.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
A. Spitaleri, S. Mari, F. Curnis, C. Traversari, R. Longhi, C. Bordignon, A. Corti, G.-. Rizzardi, G. Musco
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