Asparagine deamidation at the NGR sequence in the 5th type I repeat of fibronectin (FN-I(5)) generates isoDGR, an alpha v beta 3 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-I(5) 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 alpha v beta 3, both recapitulating canonical RGD-alpha v beta 3 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 alpha v beta 3. These findings contribute to explain the different functional properties of FN-I(5) before and after deamidation, and provide support for the hypothesis that NGR 3 isoDGR transition can work as a molecular timer for activating latent integrin-binding sites in proteins, thus regulating protein function.
STRUCTURAL BASIS FOR THE INTERATION OF ISODGR WITH RGD-BINDING SITE OF αvβ3 INTEGRIN
BORDIGNON, CLAUDIO;CORTI , ANGELO;
2008-01-01
Abstract
Asparagine deamidation at the NGR sequence in the 5th type I repeat of fibronectin (FN-I(5)) generates isoDGR, an alpha v beta 3 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-I(5) 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 alpha v beta 3, both recapitulating canonical RGD-alpha v beta 3 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 alpha v beta 3. These findings contribute to explain the different functional properties of FN-I(5) before and after deamidation, and provide support for the hypothesis that NGR 3 isoDGR transition can work as a molecular timer for activating latent integrin-binding sites in proteins, thus regulating protein function.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.