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J. Biol. Chem., Vol. 282, Issue 50, 36505-36513, December 14, 2007

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Three-dimensional Structure of the EphB2 Receptor in Complex with an Antagonistic Peptide Reveals a Novel Mode of Inhibition^*

Jill E. Chrencik, Alexei Brooun¹, Michael I. Recht, George Nicola^¶, Leila K. Davis, Ruben Abagyan^¶, Hans Widmer^||, Elena B. Pasquale^**, and Peter Kuhn²

From the Departments of Cellular Biology and ^¶Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, the Scripps-PARC Institute for Advanced Biomedical Sciences, Palo Alto Research Center, Palo Alto, California 94304, the ^||Novartis Institutes of BioMedical Research, CH-4002 Basel, Switzerland, and ^**The Burnham Institute for Medical Research, La Jolla, California 92037

The Eph family of receptor tyrosine kinases has been implicated in tumorigenesis as well as pathological forms of angiogenesis. Understanding how to modulate the interaction of Eph receptors with their ephrin ligands is therefore of critical interest for the development of therapeutics to treat cancer. Previous work identified a set of 12-mer peptides that displayed moderate binding affinity but high selectivity for the EphB2 receptor. The SNEW antagonistic peptide inhibited the interaction of EphB2 with ephrinB2, with an IC₅₀ of 15 µM. To gain a better molecular understanding of how to inhibit Eph/ephrin binding, we determined the crystal structure of the EphB2 receptor in complex with the SNEW peptide to 2.3-Å resolution. The peptide binds in the hydrophobic ligand-binding cleft of the EphB2 receptor, thus competing with the ephrin ligand for receptor binding. However, the binding interactions of the SNEW peptide are markedly different from those described for the TNYL-RAW peptide, which binds to the ligand-binding cleft of EphB4, indicating a novel mode of antagonism. Nevertheless, we identified a conserved structural motif present in all known receptor/ligand interfaces, which may serve as a scaffold for the development of therapeutic leads. The EphB2-SNEW complex crystallized as a homodimer, and the residues involved in the dimerization interface are similar to those implicated in mediating tetramerization of EphB2-ephrinB2 complexes. The structure of EphB2 in complex with the SNEW peptide reveals novel binding determinants that could serve as starting points in the development of compounds that modulate Eph receptor/ephrin interactions and biological activities.

Received for publication, August 1, 2007 , and in revised form, September 25, 2007.

The atomic coordinates and structure factors (code 2QBX) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Novartis Institutes for BioMedical Research Grant SFP-1543, National Institutes of Health Protein Structure Initiative Specialized Centers Grant GM074961 (to P. K.) and training Grant 5T32/A107354–16 (to J. C.). This is The Scripps Research Institute manuscript number 18926. 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 Fig. S1.

¹ Present address: Pfizer Inc., 10770 Science Center Dr., CB2/2213, San Diego, CA 92121.

² To whom correspondence should be addressed: 10550 N. Torrey Pines Rd., CB265, La Jolla, CA 92037. Fax: 858-784-8996; E-mail: pkuhn{at}scripps.edu.

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