Three-dimensional structure of the EphB2 receptor in complex with an antagonistic peptide reveals a novel mode of
Jill E Chrencik1, Alexei Brooun, Michael I Recht
1Department of Cellular Biology and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Abstract:
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 approximately 15 microm. 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-A 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.
Insights
Researchers elucidated the crystal structure of the EphB2 receptor bound to the SNEW peptide, revealing a novel antagonistic mechanism. This finding offers a potential scaffold for developing new cancer therapeutics targeting Eph/ephrin interactions.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Eph receptor tyrosine kinases and ephrin ligands are crucial in tumorigenesis and angiogenesis.
- Modulating Eph/ephrin interactions is a key strategy for developing cancer therapeutics.
- Previous studies identified selective peptides for EphB2, including the SNEW peptide with moderate affinity.
Purpose of the Study:
- To determine the crystal structure of the EphB2 receptor in complex with the SNEW peptide.
- To understand the molecular basis of SNEW peptide's antagonistic activity against EphB2.
- To identify potential therapeutic targets for modulating Eph/ephrin signaling.
Main Methods:
- X-ray crystallography was used to determine the EphB2-SNEW complex structure at 2.3-A resolution.
- Analysis of binding interactions and comparison with other known Eph/ligand complexes.
- Investigation of receptor dimerization in the EphB2-SNEW complex.
Main Results:
- The SNEW peptide binds to the hydrophobic ligand-binding cleft of EphB2, competitively inhibiting ephrin binding.
- The binding mode of SNEW differs from other known antagonistic peptides, indicating a novel mechanism.
- A conserved structural motif was identified across Eph/ephrin interfaces, suggesting a potential therapeutic scaffold.
- The EphB2-SNEW complex forms a homodimer, with similarities to EphB2-ephrinB2 tetramerization interfaces.
Conclusions:
- The crystal structure provides novel insights into the antagonism of Eph/ephrin interactions by the SNEW peptide.
- The identified conserved structural motif can serve as a basis for designing new therapeutic agents.
- Understanding these interactions is critical for developing targeted cancer therapies.
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