Fig. 7: The canonical two-domain activation pathway.

Without the presence of GLP-1 (upper left), the receptor is dynamic and the ECD can adopt multiple conformations (dashed circles) but favors a closed inactive state (solid green circle). The subtle dynamics of the ECD allows binding of GLP-1’s C-terminus to the ECD (upper), which triggers further dissociation of the ECD from the TMD allowing GLP-1’s N-terminus to enter the orthosteric pocket in the TMD and activate the receptor (right). Alternatively, the pre-existing small population of open conformations (solid yellow circle) can accommodate GLP-1 smoothly (lower) and then trigger the transition of GLP-1R from the closed to open conformation to accommodate the downstream G-protein (right). The ECD movements are indicated with arrows, and the closed and open conformations are colored with green and yellow backgrounds, respectively. The inactive (current structure) and active (PDB: 5VAI) TMDs are shown as blue and yellow cartoons, respectively; G protein from the active structure (PDB: 5VAI) is shown as brown cartoon. Cell membranes are shown as grey lipid bilayers.