Introduction: It is always a crucial challenge in biotechnology to avoid promiscuous binding between an anticancer peptide and multiple SH3 domains, thus reducing potential toxic effects. In spite of a great deal of experimental efforts, the association between amino acid sequence and binding specificity of peptide remained largely unknown. Aim: The purpose of this study was to optimize the amino acid sequence of peptide ligands and render high specificity towards designated therapeutic targets. Results: By exploring peptide ligands in MINT database and utilizing SH3PepInt tool for in silico peptide-target binding, here we investigated how the amino acid sequence of a peptide determined its specificity of binding to the SH3 domain of c-Src protein. We found that the 5th and the 6th residues of proline-rich motif had large influence on peptide-target binding. By purposely modifying the amino acid at these two key positons, the overall level of binding promiscuity was significantly reduced. Conclusion: Taken together, these findings corroborated that the SH3 domain of c-Src protein can discern subtle differences in the amino acid sequence of ligands, which provided a unique opportunity for rational design of therapeutic peptides.
Key words: SH3 domain, c-Src, Promiscuity, Specificity, Peptide rational design
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