Fig. 6. Activation and therapeutic targeting of peptide-binding class B GPCRs.

a The active structure of the PTH‒PTH1R‒G_s complex is presented, with components color-coded as follows: PTH (violet), PTH1R (blue), Gα_s (blue white), Gβ (orange), Gγ (magenta) and Nb35 (yellow). A structural comparison of the preactive and active states of PTH1R is shown on the right. The G protein is omitted for clarity. The conformational changes from preactive to active states are indicated with red arrows. b The active structure of PTH1R bound to PCO371 is shown. PCO371 binds to an intracellular allosteric site, distinct from the orthosteric peptide-binding pocket. PCO371 is shown as salmon-colored sticks. A zoomed-in view on the right highlights the novel binding site of PCO371. c The active structure of GLP-1R (lime) bond to GLP-1 (warm pink) is shown on the left. Superposition of the active and inactive GLP-1R structures is shown on the right (G protein omitted for clarity). ECD, which undergoes dramatic rotation upon GLP-1 binding, is shown in orange (active) and pale cyan (inactive), and the movements of the ECD and TM6 upon activation are indicated with green and red arrows, respectively. d Structures of GLP-1R bound to endogenous ligand GLP-1 and various agonist drugs are presented. A comparison of GLP-1R and GIPR structures, both bound to the dual-agonist tirzepatide, is shown on the right. Receptors are displayed as transparent surfaces with light-gray-colored cartoons, and ligands are shown as magenta cartoons.