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. 2023 Sep 6;14:5440. doi: 10.1038/s41467-023-41199-5

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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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a Consensus cryo-EM map of the M₄ mAChR (M4R) in complex with DNG_i1/Gβ₁γ₂/scFv16 bound to xanomeline resolved to 2.5 Å (FSC 0.143). The receptor is shown in green, the dominant negative (DN) heterotrimeric G_i1 protein is shown in orange, gold, and light blue for the α, β, γ subunits, respectively. Xanomeline is shown in magenta and scFv16 in silver. b Cryo-EM density (contour level 0.026) for xanomeline in the orthosteric binding site. c Xanomeline is bound in the canonical orthosteric binding site of the mAChRs positioned under a closed tyrosine lid composed of residues Y^3.33, Y^6.51 and Y^7.39. The hexyloxy tail of xanomeline sticks up towards the ECV region of the M₄ mAChR. d Comparison of the xanomeline bound active M₄ mAChR to the acetylcholine (ACh) and iperoxo (Ipx) bound M₄ mAChR (PDB: 7TRS and 7TRK, respectively). Orthosteric site residues of the xanomeline bound M₄ mAChR are shown as green sticks, residues of the ACh and Ipx bound M₄ mAChR are shown as orange and blue sticks, respectively. e Comparison of the xanomeline bound active M₄ mAChR to the Ipx bound M₁/M₂ mAChRs (M1R/M2R, PDB: 6OIJ and 6OIK, respectively). Orthosteric site residues of the xanomeline bound M₄ mAChR are shown as green sticks, residues of the Ipx bound M₁/M₂ mAChRs are shown as yellow and light blue sticks, respectively. f Comparison of the xanomeline bound active M₄ mAChR to the HTL3396 bound M₁ mAChR (PDB: 6ZG4). Orthosteric site residues of the xanomeline bound M₄ mAChR are shown as green sticks, residues of HTL3396 bound M₁ mAChR are shown as grey sticks, respectively. g Overlay of xanomeline, ACh and Ipx bound to the M₄ mAChR, Ipx bound to the M₁/M₂ mAChRs and HTL9936 bound to bound M₁ mAChR. Cross section of the h xanomeline bound M₄ mAChR orthosteric binding site, i ACh bound orthosteric M₄ mAChR binding site, j Ipx bound M₄ mAChR orthosteric binding site, k Ipx bound M₁ mAChR orthosteric binding site, l Ipx bound M₂ mAChR orthosteric binding site, m HTL3396 bound M₁ mAChR orthosteric binding site.