Figure 8. The D650V gain-of-function mutation strengthens the αC tether thereby stabilizing the kinase active conformation.
Superimposition of the crystal structures of the D650V FGFR2K mutant (in wheat), unphosphorylated autoinhibited FGFR1K (PDB ID: 1FGK [Mohammadi et al., 1996], in green), and the A-loop tyrosine phosphorylated WT FGFR2K (PDB ID: 2PVF [Chen et al., 2007], in grey). (A) Close-up views of the molecular brake regions of each of the structures. Note that the molecular brake is disengaged in the unphosphorylated D650V mutant similar to that of the A-loop phosphorylated activated FGFR2K. (B) Close-up view of the DFG latch region showing that the DFG phenylalanine in the D650V mutant adopts the same rotamer position as the corresponding phenylalanine in the A-loop tyrosine phosphorylated WT FGFR2K. (C) Close-up view of the αC tether showing enhanced hydrophobic contacts between V650 and methionines in the αC helix. (D) Comparison of the A-loop regions of the unphosphorylated D650V mutant and the A-loop tyrosine phosphorylated WT FGFR2K showing that the A-loop in the D650V mutant is primarily in the active conformation. The labels for mutant residues are in red. (E) Comparison of the A-loop region of the unphosphorylated D650V mutant and the unphosphorylated inhibited WT FGFR1K showing that the A-loop in the D650V mutant is not in the inhibited conformation. The hydrophobic interactions are represented by semitransparent mesh and solid surface, and the hydrogen bond between pY657 and R649 is shown as a black dashed line with the distance given in Å. Side chains of selected residues are shown as sticks. Atom colorings are the same as in Figure 1.