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

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

Author information

1
Dulbecco Telethon Institute Biomolecular NMR Laboratory c/o S. Raffaele Scientific Institute, 20132 Milan, Italy.

Abstract

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.

PMID:
18480047
DOI:
10.1074/jbc.M710273200
[Indexed for MEDLINE]
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