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J. Biol. Chem., Vol. 283, Issue 28, 19757-19768, July 11, 2008

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Structural Basis for the Interaction of isoDGR with the RGD-binding Site of vβ3 Integrin^*

Andrea Spitaleri¹², Silvia Mari¹, Flavio Curnis, Catia Traversari^¶, Renato Longhi^||, Claudio Bordignon^¶, Angelo Corti³, Gian-Paolo Rizzardi^¶4, and Giovanna Musco⁵

From the Dulbecco Telethon Institute Biomolecular NMR Laboratory c/o S. Raffaele Scientific Institute, 20132 Milan, the Department of Oncology, Cancer Immunotherapy and Gene Therapy Program and Italian Institute of Technology Network Research Unit of Molecular Neuroscience, S. Raffaele Scientific Institute, 20132 Milan, ^¶MolMed SpA, 20132 Milan, and ^||Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, 20131 Milan, Italy

Asparagine deamidation at the NGR sequence in the 5th type I repeat of fibronectin (FN-I₅) generates isoDGR, an vβ3 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 vβ3, both recapitulating canonical RGD-vβ3 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 vβ3. 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.

Received for publication, December 18, 2007 , and in revised form, May 7, 2008.

^* This work has been supported in part by MolMed SpA. C. T., C. B., and G. P. R. are MolMed employees, and A. C. and G. M. are consultants of MolMed. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3 and Tables S1-S3.

¹ Both authors contributed equally to this work.

² Supported by FIRB Grant RBIP06FYF7.

³ To whom correspondence may be addressed: MolMed, via Olgettina 58, 20132 Milan, Italy. Fax: 39.02.2643.4786; E-mail: corti.angelo{at}hsr.it.

⁴ To whom correspondence may be addressed: MolMed, via Olgettina 58, 20132 Milan, Italy, Fax: +39.02.2127.7325; E-mail: paolo.rizzardi{at}molmed.com.

⁵ Supported by Telethon Foundation. To whom correspondence may be addressed: via Olgettina 58, 20132 Milan, Italy. Fax: 39.02.2643.4153; E-mail: musco.giovanna{at}hsr.it.

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