TY - JOUR
T1 - Structural basis for the interaction of isoDGR with the RGD-binding site of αvβ3 integrin
AU - Spitaleri, Andrea
AU - Mari, Silvia
AU - Curnis, Flavio
AU - Traversari, Catia
AU - Longhi, Renato
AU - Bordignon, Claudio
AU - Corti, Angelo
AU - Rizzardi, Gian Paolo
AU - Musco, Giovanna
PY - 2008/7/11
Y1 - 2008/7/11
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M710273200
DO - 10.1074/jbc.M710273200
M3 - Article
C2 - 18480047
AN - SCOPUS:50349095214
VL - 283
SP - 19757
EP - 19768
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 28
ER -