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. 2023 May 3;617(7960):417–425. doi: 10.1038/s41586-023-06030-7

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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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Fig. 2 — a, The binding poses of momSalB and GR89,696 in their respective complex structures. The salt bridge or H-bond interactions in G_z- and G_g-coupled structures are shown as black dashed lines. This salt bridge or H-bond interaction is absent in momSalB-bound KOR. b, The highly conserved anchoring residue Asp138^3.32 has a different role in momSalB, GR89,696 or U50,488-mediated KOR activation. Data are normalized to the percentage of the reference agonist U50,488. Data are grouped data ± s.e.m. of n = 3 biological replicates. The full quantification parameters for this experiment are provided in Supplementary Table 1. c, Specific residues in the orthosteric pockets that interact with momSalB or GR89,696. Note that the I135^3.29L mutation was included in KOR structure constructs to increase the expression level. d, Mutagenesis screening of binding-pocket residues using G-protein-mediated cAMP inhibition assays. The effect on the potency of momSalB or GR89,696 was quantified on the basis of the log[EC₅₀] values. Data are log[EC₅₀] ± s.e.m. of n = 3 biological replicates. Statistical significance for each mutant was calculated using one-way analysis of variance (ANOVA) with Dunnett’s multiple-comparison test compared with the wild type (WT); *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; NS, not significant. GR89,696: P = 0.016 (V230A), P = 0.0008 (H291A), P = 0.1758 (V134A), P = 0.9814 (Q115N), P = 0.006 (V108A), P = 0.1165 (I316A); momSalB: P = 0.344 (D138N), P = 0.0009 (W124A), P = 0.0064 (V134A), P = 0.0068 (Q115N), P = 0.0002 (I135A). The full quantification parameters for this experiment are provided in Supplementary Table 2.