Structural basis for the interaction of isoDGR with the RGD-binding site of αvβ3 integrin

Andrea Spitaleri, Silvia Mari, Flavio Curnis, Catia Traversari, Renato Longhi, Claudio Bordignon, Angelo Corti, Gian Paolo Rizzardi, Giovanna Musco

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)19757-19768
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number28
DOIs
Publication statusPublished - Jul 11 2008

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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