Figure 2

Surface loops in the SH2 domain confer multiple binding modes to the tyrosine phosphatase SHP2. The N-terminal SH2 (N-SH2), C-terminal SH2 (C-SH2) and the phosphatase domains are coloured in light blue, orange, and cyan, respectively. The EF and BG loops of the N-SH2 domain are coloured brown and magenta, respectively. Molecular orientation is aligned for the N-SH2 domain, and drawn to scale. (A) The inhibitory state of SHP2 (PDB ID: 2SHP) [87]. The DE loop region of the N-SH2 domain, including the side chain of Asp61 (coloured red), mimics a pTyr substrate and blocks the active site of the phosphatase domain. In this conformation, the BG loop contacts the EF loop and inhibits ligand binding. (B) The 1:1 binding mode (PDB ID: 3TL0) [90]. The bound LNpYAQLW peptide is coloured yellow. The C-terminal region of the single peptide binds to a cleft between the EF and BG loops. (C) The 1:2 binding mode, in which the two identical peptides, with a sequence VIpYFVPL, form a short, antiparallel β-sheet and bind to a single SH2 domain (PDB ID: 3TKZ) [90]. The BG loop is positioned to accommodate the two peptides.