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

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Extended Data Fig. 10 — (a) A cross-section view of the PCO371-bound PTH1R. (b) A magnified view of the superimposed structure of PCO371-bound PTH1R (purple), GCG-bound GCGR (orange), and GIP-bound GIPR (gray). (c) Structural comparison of N^5.50 of PCO371-insensitive receptors and PCO371-sensitive receptors, related to Fig. 4d. Violet, PCO371-bound PTH1R; gray, PCO371-insensitive receptors; orange, PCO371-sensitive receptors. (d) Trajectory analysis of three independent simulations with PCO371-bound PTH1R. The top two panels show that PCO371-bound PTH1R maintains an active conformation, resembling our cryo-EM structure. The panel second from the bottom shows the dihedral angle of N374^5.50. The angles of PCO371-bound PTH1R (blue) and GLP-1R (red) are shown as dash lines. The bottom panel shows the distance between N374^5.50-ND2 and PCO371-O1, representing stably PCO371 interaction with N374^5.50 in an intermediate state. (e) Distinct conformation of N374^5.50 between PCO371-bound PTH1R and GLP-1-bound active GLP-1R (PDB ID: 6X18). The dihedral angle is calculated with the N–Cα and Cβ–Cγ angles of N^5.50. (f) Superimposition of our cryo-EM structure (violet) and a representative snapshot of 1.5 µs MD simulation in run 2 of PCO371-bound PTH1R (yellow). In the simulation, the receptor adopted an intermediate structure, and PCO371 moved toward TM5. (g) Comparison of our cryo-EM structure (violet) and an intermediate structure (yellow) observed in the simulation. PCO371 does not interact with N374^5.50 in our cryo-EM structure, while it creates a stable interaction with N374^5.50 in the simulation. (h) cAMP accumulation of WT and N374^5.50A mutant with PTH and PCO371. The N374^5.50A mutant selectively reduced PCO371 response. Symbols and error bars represent mean and SEM, respectively, and dots show individual data of three independent experiments, with each performed in duplicate. * and ** represent P < 0.05 and 0.01, respectively, with two-way ANOVA followed by Dunnett’s test for multiple comparison analysis. ns, not significantly different between the groups.