Skip to main content
. 2023 Jun 7;618(7967):1085–1093. doi: 10.1038/s41586-023-06169-3

Extended Data Fig. 9. Structural comparison of PCO371-bound PTH1R and the other intracellular ligands-bound GPCR structures.

Extended Data Fig. 9

(a) TMD structures of PCO371-bound PTH1R and six intracellular ligand-bound GPCRs are shown parallel to the membrane or from the intracellular side. Violet, PCO371-bound PTH1R; magenta, PCO371; orange, compound 2-bound GLP-1R; blue, compound 2, yellow, C-C motif chemokine receptor (CCR2)-RA-[R]-bound CCR2; violet, CCR2-RA-[R]; yellow-green, cmpd2105-bound CCR7; plum, cmpd2105; green, vercirnon-bound CCR6; brown, vercirnon; powder blue, cmpd-15PA-bound β2AR; coral, cmpd-15PA; light cyan, cmpd-6FA-bound β2AR; gold, cmpd-6FA. (b, c) Superimposed structures of compound2-bound GLP-1R, GLP-1-bound GLP-1R, LY3502970-bound GLP-1R, and inactive GLP-1R. White, GLP-1-bound GLP-1R; khaki, GLP-1; red, LY3502970 -bound GLP-1R; sky blue, LY3502970; gray, inactive GLP-1R. Compound2 binds with the intracellular portion of TM6, and compound2-bound GLP-1R exhibits the identical active conformation of TM6. (d) GloSensor cAMP responses in wild-type (WT) PTH1R and the TM6-replaced mutants upon endogenous agonists (PTH or glucagon) or PCO371 stimulation. Symbols and error bars represent mean and SEM, respectively, of three independent experiments with each performed in duplicate. (e) Cut-through view of PCO371–PTH1R–Gs and magnified view of the PCO371-G-protein interface. The PCO371-interacting Gαs region is colored orange. (f) Sequence alignment of the C-terminal hook of Gα proteins.