Extended Data Fig. 7: GLP-1R domains are stabilized by either ligand contacts or lipid interactions.
From: Activation of the GLP-1 receptor by a non-peptidic agonist
a, Top, RMSF values of alpha carbons computed during MD simulations of the GLP-1R–GLP-1–Gs complex (black line) and the GLP-1R–TT-OAD2–Gs complex (red line); transmembrane helices, intracellular loops (ICLs), and ECLs positions are indicated. Bottom left, RMSF values plotted on the GLP-1R structure bound to GLP-1 (transparent ribbon). Bottom right, RMSF values plotted on the GLP-1R structure bound to TT-OAD2 (transparent stick representation). ECL1 and ECL3 were more dynamic in the GLP-1-bound receptor than the TT-OAD2-bound structure. By contrast, ECL2 and the top end of TM5 were more mobile in the GLP-1R–TT-OAD2–Gs complex. b, GLP-1R contacts formed with membrane lipids during molecular dynamic simulations of the GLP-1R–TT-OAD2–Gs and the GLP-1R–GLP-1–Gs systems. Two sides views of the receptor are shown (ribbon and transparent surface). When bound to TT-OAD2, ECL1, TM3, the distal end of TM6, and ECL3 are more in contact with the membrane lipids (magenta). By contrast, TM1 and TM7 are more prone to interact with the membrane when GLP-1 is bound (green). The outward movement of ECL3 in the GLP-1R–TT-OAD2–Gs complex (stabilized by a hydrogen bond network different than GLP-1R–GLP-1–Gs; Extended Data Table 2) produces more interactions with the lipids, possibly further stabilizing the open conformation of TM6, ECL3 and TM7.
