Fig. 6: Proposed structural mechanism underlying cooperative binding and inhibition synergy.
From: Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors
When bound to nucleotide, the phosphates force the P-loop to be in an extended conformation with the side chain of F723 outward (grays, labeled 1 and 3). When bound to a TKI (osimertinib shown, magenta), F723 often folds under the P-loop (black, labeled 2) where the phosphates of ATP would be located. When in complex with both TKI and an allosteric inhibitor (green), the P-loop folds down into the space usually occupied by the phosphates and the side chain of F723 forms a π-stacking interaction with the inhibitor (light gray, labeled 4), closing the putative exit tunnel (see Fig. 4c). This more compact ternary complex conformation facilitates cooperative binding, which leads to inhibition synergy.
