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SH3 domains are protein recognition modules within many adaptors and enzymes. With more than 500 SH3 domains in the human genome, binding selectivity is a key issue in understanding the molecular basis of SH3 domain interactions. The Grb2-like adaptor protein Mona/Gads associates stably with the T-cell receptor signal transducer SLP-76. The crystal structure of a complex between the C-terminal SH3 domain (SH3C) of Mona/Gads and a SLP-76 peptide has now been solved to 1.7 A. The peptide lacks the canonical SH3 domain binding motif P-x-x-P and does not form a frequently observed poly-proline type II helix. Instead, it adopts a clamp-like shape around the circumfence of the SH3C beta-barrel. The central R-x-x-K motif of the peptide forms a 3(10) helix and inserts into a negatively charged double pocket on the SH3C while several other residues complement binding through hydrophobic interactions, creating a short linear SH3C binding epitope of uniquely high affinity. Interestingly, the SH3C displays ion-dependent dimerization in the crystal and in solution, suggesting a novel mechanism for the regulation of SH3 domain functions.

Original publication




Journal article



Publication Date





2571 - 2582


Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, Carrier Proteins, Crystallography, X-Ray, Dimerization, Humans, Hydrogen Bonding, In Vitro Techniques, Mice, Models, Molecular, Molecular Sequence Data, Phosphoproteins, Phylogeny, Protein Binding, Recombinant Proteins, Sequence Homology, Amino Acid, Static Electricity, src Homology Domains