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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. 4 — (a) Comparison of the PCO371–PTH1R–G_s complex with endogenous peptide-bound and orthosteric chemical agonist-bound class B1 GPCR complexes. Because there is no structure of orthosteric chemical agonist-bound PTH1R structure, we used LY3502970 (a proprietary GLP-1 receptor agonist)–GLP-1R–G_s to represent the structures of orthosteric chemical agonist-bound class B1 GPCRs. Orthogonal views and models show PTH–PTH1R–G_s (PDB: 7VVL), PCO371–PTH1R–G_s (8GW8), and LY3502970–GLP-1R–G_s (PDB: 6XOX). Green, PTH-bound PTH1R; orange, PTH; yellow, mini-G_s Ras-like domain; tomato, Gβ₁; navy, Gγ₂; powder blue, Nb35; violet, PCO371-bound PTH1R; crimson, LY3502970-bound GLP-1R; sky blue, LY3502970. Gray, PTH–PTH1R–G_s; violet, PCO371–PTH1R–G_s; red, LY3502970–GLP-1R–G_s. The PCO371-bound PTH1R map shows no obvious ligand-like density in the orthosteric pocket, in contrast to the PTH-bound PTH1R and LY3502970-bound GLP-1R maps. (b) Cut-through views of endogenous peptide-bound PTH1R and GLP-1R structures and chemical agonist-bound GLP-1R structures. Green, PTH-bound PTH1R; orange, PTH; white, GLP-1R; yellow-green, GLP-1; violet, PCO371-bound PTH1R; crimson, PCO371; yellow, CHU-128-bound GLP-1R; blue-violet, CHU-128; purple, danuglipron (PF-06882961)-bound GLP-1R; khaki, PF-06882961; red, LY3502970-bound GLP-1R; sky blue, LY3502970. Only PCO371 binds within the intracellular cavity, whereas other agonists bind in various ways to the orthosteric pocket.