Figure 5.

(R)-5-OH-DPAT forms a meta-stable binding mode with S193^5.42. (A) Clustering simulations of (R)-5-OH-DPAT in complex with WT D₂R, based on the RMSD of the ligand, reveal two binding modes. The main binding mode was maintained over 56% of the simulation frames (green) and a meta-stable binding mode was maintained over 15% of the simulation frames (red). (B,C). For each of the binding modes, the studied position S193^5.42, as well as residues that form polar interactions with the ligand, are shown. These polar interactions are highlighted with red lines. (D) A model explaining the slow K_off values observed for the unbinding of (R)-5-OH-DPAT from WT D₂R. Before dissociating from the receptor (purple conformation), (R)-5-OH-DPAT bound in the main binding mode (green) assumes a meta-stable binding mode (red). When bound in this meta-stable binding mode, (R)-5-OH-DPAT can revert to the main binding mode or proceed to an unbound conformation. Hence, the dissociation of (R)-5-OH-DPAT is effectively slowed down by S193^5.42. In comparison, at the S193^5.42A mutant receptor, the absence of the meta-stable binding mode permits fast exchange between the bound and unbound conformations of (R)-5-OH-DPAT.