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Sci. Signal., 25 September 2012
Vol. 5, Issue 243, p. ra68
[DOI: 10.1126/scisignal.2003021]

RESEARCH ARTICLES

Editor's Summary

Higher Affinity Inhibits Signaling
The interaction of peptide motifs and peptide-binding domains is critical for cell signaling. Kaneko et al. generated mutant Src homology 2 (SH2) domains with unnaturally high affinities for phosphotyrosine peptide motifs, which they called "superbinders." Crystal structures of a superbinder bound to a peptide with a phosphotyrosine revealed a two-part mode of binding, with the mutated residues forming an additional interaction surface for the phosphorylated tyrosine that was not present in wild-type, ligand-bound SH2 domains. Expressing these superbinder SH2 domains in mammalian cells inhibited epidermal growth factor receptor signaling and cell growth, suggesting that these domains may be effective tools for limiting aberrant phosphotyrosine-mediated signaling associated with disease.

Citation: T. Kaneko, H. Huang, X. Cao, X. Li, C. Li, C. Voss, S. S. Sidhu, S. S. C. Li, Superbinder SH2 Domains Act as Antagonists of Cell Signaling. Sci. Signal. 5, ra68 (2012).

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