SH3 domain (Src Homology 3)

The SH3 domain from phosphatidylinositol 3-kinase is colored red. It is a barrel-like all-beta strand domain. It is shown bound to a 12 residue proline-rich peptide. The peptide binds along the side of the barrel, and not at one end. It forms a polyproline-II left-handed helix. The proline residues are colored cyan.

Structural studies of the phosphatidylinositol 3-kinase (PI3K) SH3 domain in complex with a peptide ligand: role of the anchor residue in ligand binding.
Batra-Safferling R, Granzin J, Mödder S, Hoffmann S, Willbold D.
Biol Chem. 2010 Jan;391(1):33-42.

(PubMed)

3i5r (PDB)

SH3 domain ligand binding: What's the consensus and where's the specificity?
Saksela K, Permi P.
FEBS Lett. 2012 Aug 14;586(17):2609-14. doi: 10.1016/j.febslet.2012.04.042. Epub 2012 May 2. Review.

Abstract
An increasing number of SH3 domain-ligand interactions continue to be described that involve the conserved peptide-binding surface of SH3, but structurally deviate substantially from canonical docking of consensus motif-containing SH3 ligands. Indeed, it appears that that the relative frequency and importance of these types of interactions may have been underestimated. Instead of atypical, we propose referring to such peptides as type I or II (depending on the binding orientation) non-consensus ligands. Here we discuss the structural basis of non-consensus SH3 ligand binding and the dominant role of the SH3 domain specificity zone in selective target recognition, and review some of the best-characterized examples of such interactions.

The SH3 domain--a family of versatile peptide- and protein-recognition module.
Kaneko T, Li L, Li SS.
Front Biosci. 2008 May 1;13:4938-52. Review.

Abstract
Src homology 3 (SH3) domains were initially characterized as a prevalent protein module that recognizes proline-rich sequences, in particular those containing a PxxP motif. Recent studies have shown that the specificity and cellular function of SH3 domains are far more diverse than previously appreciated. Despite lacking distinguishing features, the ligand-binding surface of an SH3 domain can be molded to accommodate a variety of peptide ligands. Moreover, certain SH3 domains are capable of using surfaces distinct from the canonical ligand-binding site to engage a peptide or protein. The identification of novel motifs and domains recognized by the SH3 domain greatly expands the ligand pool and cellular function for this family. However, this also imposes the question as to how the specificity of the hundreds of human SH3 domains is regulated in a cell to ensure their proper functions. Here we review literature on the specificity of SH3 domains, with an emphasis on the structural basis of ligand recognition, and discuss mechanisms employed by SH3 domain-containing proteins to execute defined cellular functions through highly regulated SH3-ligand interactions.