SH2 / phosphopeptide complex

Shikimate 3-phosphate 687s SH2 / phosphopeptide complex 368s Sialic acid 165s, 183, 546 Sialidase 186... 

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. 

Information about the specificity of SH2 domain binding came initially from the structures of the Src and Lck SH2 domains in complex with tyrosyl phosphopeptides with the sequence Glu, Glu, He (EEI) C-ter-minal to the pTyr (pY) (Eck et al., 1993 Waksman et al., 1993). This pYEEI sequence had previously been identified to be specific for the Src family of SH2 domains, which includes Lck (see Section III). The Src and Lck structures are very similar to one another. Although the peptides employed in both studies contained residues outside the pYEEI motif, the structures indicate that only these four residues contact the SH2 domain. The peptide binds the SH2 domains perpendicular to the central p-sheet in an extended conformation (Fig. 2A). The pTyr makes contacts very similar to those observed for the structure of the Src SH2 domain in complex with low-affinity tyrosyl phosphopeptides (see above). However, in addition, the EEI motif makes specific contact with other residues of the protein. 

The nuclear magnetic resonance (NMR) structure of the C-PLCy SH2 domain in complex with a tyrosyl phosphopeptide from the PDGFR has also revealed that an extended groove forms the binding interface (Fig. 2E (Pascal et al., 1994). Here, the groove is also relatively hydrophobic in nature. This presumably allows the SH2 domain to bind the hydrophobic residues of the ligand C-terminal to the pTyr (-1-1 He, +2... 

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