Fig. 5: Mutational effects that alter WPD loop conformational dynamics.

a Residues with consistent gain-of-function mutational effects around the WPD loop (PDB code 3ZM0). b Frame from MD trajectory of SHP2 starting from PDB 6CRF, showing packing of W423, P424, P429, and F469 in WPD loop open conformation. F469 points towards the WPD loop in this structure. c Frame from an MD trajectory starting from PDB 6CRF, showing that, in the WPD-closed conformation, W423 displaces F469, and P424 is released from its intimate packing in the turn of the loop. d Three MD trajectories starting from the open conformation, showing coordinated movements between F469, W423, and P424. The first trajectory is an example of these movements culminating in WPD closure. The second trajectory also shows WPD loop closure, but more gradually. The third trajectory shows coupled F469, W423, and P424 motions that revert back to their starting state, resulting in no WPD loop closure. F469 rotation is quantified by the χ₁ angle of this residue. W423 reorientation is quantified by the distance between W423 Cζ₃ and P429 Cγ. P424 packing is quantified by the distance between P424 Cγ and the V428 carbonyl. WPD loop closure is quantified by the distance between the D425 and C459 Cα atoms. Gray shaded segments denote F469 in a permissive state for WPD loop closure. Pink shaded segments denote WPD loop closure. e Small residue T356 (blue) permits F469 rotation in SHP2, restricting W423 rotation and WPD loop closure (PDB code 3ZM0, top). Multiple F469 rotamers are modeled in this crystal structure. Bulky residue L110 (blue) constrains F225 rotation in PTP1B, permitting facile W179 rotation and WPD loop closure (PDB code 5K9V, bottom).