Fig. 4. S1PR1 activation mechanism.

a Superposition of S1PR1 structures in inactive (gray; PDB code: 3V2Y) and Gi-stabilized active states (teal). Notable conformational changes occur at intracellular ends of TM6 and TM7 upon receptor activation. b Detailed comparison of the orthosteric binging pocket of antagonist ML056 (dodger blue)-bound inactive S1PR1 with that of agonist siponimod-bound active S1PR1. In particular, side-chains of the residues L128^3.36, F210^5.47, W269^6.48, F273^6.52 and L297^7.39 are observed to exhibit a notable displacement upon activation. c The toggle molecular switch L128^3.36 and W269^6.48 in S1PR1. The left panel displays relative orientation of L128^3.36–W269^6.4 in inactive S1PR1, whereas the right panel represents movement of L128^3.36–W269^6.4 when sensing agonist. d The key D/E–R^3.50–Y and N–P^7.50–xx–Y^7.53 motifs important for activation of S1PR1 are observed to display conformational rearrangement in activated receptor.