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J. Biol. Chem., Vol. 282, Issue 13, 9657-9665, March 30, 2007

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Structure-Function Analysis of Arg-Gly-Asp Helix Motifs in v6 Integrin Ligands^*

Danielle DiCara, Chiara Rapisarda^¶, Julie L. Sutcliffe^||, Shelia M. Violette^**, Paul H. Weinreb^**, Ian R. Hart, Mark J. Howard^¶12, and John F. Marshall¹³

From the Tumour Biology Centre, Cancer Research UK Clinical Centre, Queen Mary's College, Barts and the London Medical and Dental School, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom, ^¶Protein Science Group, Department of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, United Kingdom, the ^||Department of Biomedical Engineering, University of California, Davis, California 95616–5294, and ^**Biogen Idec Inc., Cambridge Center, Cambridge, Massachusetts 02142

Data relating to the structural basis of ligand recognition by integrins are limited. Here we describe the physical requirements for high affinity binding of ligands to v6. By combining a series of structural analyses with functional testing, we show that 20-mer peptide ligands, derived from high affinity ligands of v6 (foot-and-mouth-disease virus, latency associated peptide), have a common structure comprising an Arg-Gly-Asp motif at the tip of a hairpin turn followed immediately by a C-terminal helix. This arrangement allows two conserved Leu/Ile residues at Asp⁺¹ and Asp⁺⁴ to be presented on the outside face of the helix enabling a potential hydrophobic interaction with the v6 integrin, in addition to the Arg-Gly-Asp interaction. The extent of the helix determines peptide affinity for v6 and potency as an v6 antagonist. A major role of this C-terminal helix is likely to be the correct positioning of the Asp⁺¹ and Asp⁺⁴ residues. These data suggest an explanation for several biological functions of v6 and provide a structural platform for design of v6 antagonists.

Received for publication, November 9, 2006 , and in revised form, January 16, 2007.

^* 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. 1–7 and Tables 1–3.

¹ Both authors should be considered as senior authors.

² To whom correspondence may be addressed. Tel.: 44-0207-014-0400; Fax: 44-0207-014-0401; E-mail: m.j.howard{at}kent.ac.uk. ³ To whom correspondence may be addressed. Tel.: 44-0207-014-0400; Fax: 44-0207-014-0401; E-mail: john.marshall{at}cancer.org.uk.

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