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Growth arrest specific 7 (Gas7) protein is a cytoskeleton regulator playing a crucial role in neural cell development and function, and has been implicated in Alzheimer disease, schizophrenia and cancers. In human, three Gas7 isoforms can be expressed from a single Gas7 gene, while only the longest isoform, hGas7c, possesses an SH3 domain at the N-terminus. To date, the structure and function of hGas7 SH3 domain are still unclear. Here, we reported the solution NMR structure of hGas7 SH3 domain (hGas7-SH3), which displays a typical SH3 β-barrel fold comprising five β-strands and one 3 10 -helix. Structural and sequence comparison showed that hGas7-SH3 shares high similarity with Abl SH3 domain, which binds to a high-affinity proline-rich peptide P41 in a canonical SH3-ligand binding mode through two hydrophobic pockets and a specificity site in the RT-loop. However, unlike Abl-SH3, only six residues in the RT-loop and two residues adjacent to but not in the two hydrophobic pockets of hGas7-SH3 showed significant chemical shift perturbations in NMR titrations, suggesting a low affinity and a non-canonical binding mode of hGas7-SH3 for P41. Furthermore, four peptides selected from phage-displayed libraries also bound weakly to hGas7-SH3, and the binding region of hGas7-SH3 was mainly located in the RT-loop as well. The ligand identifications through structural similarity searching and peptide library screening in this study imply that although hGas7-SH3 adopts a typical SH3 fold, it probably possesses distinctive ligand-binding specificity. • Human Gas7 SH3 domain adopts a typical SH3 β-barrel fold. • hGas7-SH3 exhibits highly structural similarity with Abl SH3 domain. • hGas7-SH3 binds weakly with peptide P41 and the peptides selected via phage display. • The RT-loop of hGas7-SH3 is important for ligand binding. • hGas7-SH3 may bind with ligands through a non-canonical mode. [ABSTRACT FROM AUTHOR]