title: Structural basis for the interaction of isoDGR with the RGD-binding site of alphavbeta3 integrin.
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.
authors.affiliation: Dulbecco Telethon Institute Biomolecular NMR Laboratory c/o S. Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Spitaleri
authors.forename: Silvia
authors.initials: S
authors.lastname: Mari
authors.forename: Flavio
authors.initials: F
authors.lastname: Curnis
authors.forename: Catia
authors.initials: C
authors.lastname: Traversari
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.forename: Gian-Paolo
authors.initials: GP
authors.lastname: Rizzardi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Musco
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D001665:Binding Sites / Q000502:physiology; D045744:Cell Line, Tumor; D003641:Deamination; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology
chemical_list: D005353:Fibronectins; D039302:Integrin alphaVbeta3; C526428:NGR peptide; D009842:Oligopeptides