9.A.14.4.11
Parathyroid hormone/parathyroid hormone-related peptide-1 receptor, PTH1R, of 573 aas and 8 or 9 TMSs in a 1 + 7 or 8 TMS arrangement. PTH1R is a class B G protein-coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and hypoparathyroidism. Zhao et al. 2019 reported the cryo-EM structure of human PTH1R bound to a long-acting PTH analog and the stimulatory G protein. The bound peptide adopted an extended helix with its amino terminus inserted deeply into the receptor TMS, which led to partial unwinding of the carboxyl terminus of TMS6 and induceed a sharp kink at the middle of this helix to allow the receptor to couple with the G protein, while the extracellular domain adopted multiple conformations (Zhao et al. 2019). A cryoEM structure of a complex of G(s) and the human parathyroid hormone type 1 receptor (PTH1R) bound to a PTH1R agonist, PCO371 has been reported (Kobayashi et al. 2023). PCO371 binds within an intracellular pocket of PTH1R and directly interacts with G(s). The PCO371-binding mode rearranges the intracellular region towards the active conformation without extracellularly induced allosteric signal propagation (Kobayashi et al. 2023). PCO371 stabilizes the outward-bent conformation of TMS 6, which facilitates binding to G proteins rather than beta-arrestins. Furthermore, PCO371 binds within the conserved intracellular pocket, activating 7 out of the 15 class B1 GPCRs (Kobayashi et al. 2023). Thus, class B1 GPCR activation is mediated by an intracellular agonist.

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