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Peptide Scanning-assisted Identification of a Monoclonal Antibody-recognized Linear B-cell Epitope
Published on: March 24, 2017
Investigation of the interactions between the EphB2 receptor and SNEW peptide variants
Buyong Ma1, Stephanie Kolb, Michael Diprima
1Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, National Cancer Institute , Frederick, MD , USA .
Abstract:
EphB2 interacts with cell surface-bound ephrin ligands to relay bidirectional signals. Overexpression of the EphB2 receptor protein has been linked to different types of cancer. The SNEW (SNEWIQPRLPQH) peptide binds with high selectivity and moderate affinity to EphB2, inhibiting Eph-ephrin interactions by competing with ephrin ligands for the EphB2 high-affinity pocket. We used rigorous free energy perturbation (FEP) calculations to re-evaluate the binding interactions of SNEW peptide with the EphB2 receptor, followed by experimental testing of the computational results. Our results provide insight into dynamic interactions of EphB2 with SNEW peptide. While the first four residues of the SNEW peptide are already highly optimized, change of the C-terminal end of the peptide has the potential to improve SNEW-binding affinity. We identified a PXSPY motif that can be similarly aligned with several other EphB2-binding peptides.
Insights
The SNEW peptide inhibits cancer-linked EphB2 receptor activity. Computational and experimental studies show modifying the peptide
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Research
- Computational Chemistry
Background:
- EphB2 receptor tyrosine kinase signaling is crucial for cellular communication.
- Aberrant EphB2 signaling and overexpression are implicated in various cancers.
- The SNEW peptide selectively targets EphB2, inhibiting its interaction with ephrin ligands.
Purpose of the Study:
- To computationally re-evaluate and experimentally validate the binding interactions of the SNEW peptide with the EphB2 receptor.
- To understand the dynamic interplay between SNEW peptide and EphB2.
- To identify strategies for enhancing the binding affinity of SNEW peptide to EphB2.
Main Methods:
- Free energy perturbation (FEP) calculations were employed to model SNEW-EphB2 interactions.
- Computational findings were subsequently validated through experimental testing.
- Analysis of peptide-receptor dynamics and identification of key binding motifs.
Main Results:
- FEP calculations provided detailed insights into the dynamic binding of SNEW peptide to EphB2.
- The N-terminal portion (first four residues) of SNEW peptide demonstrated high optimization.
- Modifications at the C-terminal end of the peptide present an opportunity to improve binding affinity.
- A conserved PXSPY motif was identified across multiple EphB2-binding peptides.
Conclusions:
- The study elucidates the molecular basis of SNEW peptide binding to EphB2.
- Optimizing the C-terminal region of SNEW peptide can enhance its therapeutic potential.
- The identified PXSPY motif may serve as a target for developing novel EphB2 inhibitors.
- These findings contribute to the development of targeted cancer therapies by modulating EphB2 signaling.
