Single SH2 Domain Structure

The first SH2 domain structures to be solved were those of the Src tyrosine kinase (Waksman et al., 1992), the Abl tyrosine kinase (Overduin et al., 1992), and the N-terminal SH2 domain of the p85 subunit of the PI 3 -kinase (N-p85 SH2 domain) (Booker et al., 1992). These structures revealed the architecture of SH2 domains. The SH2 domain fold is relatively simple it consists of a central antiparallel (3-sheet flanked by 

The structure of SH2 domains can be conveniendy divided into two functional regions that involved in coordination of the pTyr of the target and that which contacts the residues G-terminal to the pTyr (Fig. 2A). The pTyr binding cavity is found in the N-terminal half of the protein between the central p-sheet and helix oA, while the specificity determining region is found primarily in the C-terminal half of the protein between the central p-sheet and hehx aB (Fig. 2A). Each of these regions is described in detail below. 

The structure of the Src SH2 domain in complex with two low-affinity tyrosyl phosphopeptides elucidated the structural basis for pTyr recognition by SH2 domains (Waksman et al., 1992). The pTyr is stabilized by a dense network of hydrogen bonds and ionic interactions contributed by SH2 domain residues forming a deep cavity, the pTyr binding pocket (Fig. 2B). Most noteworthy, a universally conserved arginine residue (Arg PB5) at the center and base of the cavity makes a bidentate ionic interaction with two oxygens of the phosphate group. Arg pB5 is nearly completely solvent inaccessible in the free form of the protein. In the bound form, the ionic interaction which Arg pB5 makes with the phosphate is also entirely removed from solvent. 

Two other positively charged residues are located in the pTyr binding pocket of the Src SH2 domain Arg oA2 and Lys pD6 (Fig. 2B). Arg aA2 interacts with the phosphate group and also makes an unusual amino-aromatic interaction with the phenol ring of the pTyr. This type of 

While the interactions at the pTyr binding pocket are generally similar for all SH2 domains, those which involve residues other than pTyr are not. These interactions help to determine the specificity of SH2 domain-target recognition. Comparison of the many SH2 domain-phosphopeptide structures has revealed that different SH2 domains use somewhat different mechanisms to engage their respective targets. 

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