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- EMDB-48108: Focused refinement of M5 Muscarinic acetylcholine receptor in com... -

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Entry
Database: EMDB / ID: EMD-48108
TitleFocused refinement of M5 Muscarinic acetylcholine receptor in complex with agonist acetylcholine and positive allosteric modulator VU6007678
Map dataFocused refinement of M5 Muscarinic acetylcholine receptor in complex with agonist acetylcholine and positive allosteric modulator VU6007678
Sample
  • Complex: Human M5-miniGq-Gb1g2 complex
KeywordsG protein-coupled receptor / acetylcholine binding / seven transmembrane protein / MEMBRANE PROTEIN / SIGNALING PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.11 Å
AuthorsBurger WAC / Mobbs JI / Thal DM
Funding support Australia, 2 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1196951 Australia
Australian Research Council (ARC)LP180100560 Australia
CitationJournal: Nat Commun / Year: 2025
Title: Cryo-EM reveals an extrahelical allosteric binding site at the M mAChR.
Authors: Wessel A C Burger / Jesse I Mobbs / Bhavika Rana / Jinan Wang / Keya Joshi / Patrick R Gentry / Mahmuda Yeasmin / Hariprasad Venugopal / Aaron M Bender / Craig W Lindsley / Yinglong Miao / ...Authors: Wessel A C Burger / Jesse I Mobbs / Bhavika Rana / Jinan Wang / Keya Joshi / Patrick R Gentry / Mahmuda Yeasmin / Hariprasad Venugopal / Aaron M Bender / Craig W Lindsley / Yinglong Miao / Arthur Christopoulos / Celine Valant / David M Thal /
Abstract: The M muscarinic acetylcholine receptor (M mAChR) represents a promising therapeutic target for neurological disorders. However, the high conservation of its orthosteric binding site poses ...The M muscarinic acetylcholine receptor (M mAChR) represents a promising therapeutic target for neurological disorders. However, the high conservation of its orthosteric binding site poses significant challenges for drug development. While selective positive allosteric modulators (PAMs) offer a potential solution, a structural understanding of the M mAChR and its allosteric binding sites remains limited. Here, we present a 2.8 Å cryo-electron microscopy structure of the M mAChR complexed with heterotrimeric G protein and the agonist iperoxo, completing the active-state structural characterization of the mAChR family. To identify the binding site of M-selective PAMs, we implement an integrated approach combining mutagenesis, pharmacological assays, structural biology, and molecular dynamics simulations. Our mutagenesis studies reveal that selective M PAMs bind outside previously characterized M mAChR allosteric sites. Subsequently, we obtain a 2.1 Å structure of M mAChR co-bound with acetylcholine and the selective PAM VU6007678, revealing an allosteric pocket at the extrahelical interface between transmembrane domains 3 and 4 that is confirmed through mutagenesis and simulations. These findings demonstrate the diverse mechanisms of allosteric regulation in mAChRs and highlight the value of integrating pharmacological and structural approaches to identify allosteric binding sites.
History
DepositionNov 30, 2024-
Header (metadata) releaseAug 13, 2025-
Map releaseAug 13, 2025-
UpdateAug 26, 2026-
Current statusAug 26, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48108.png

Downloads & links

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Map

FileDownload / File: emd_48108.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFocused refinement of M5 Muscarinic acetylcholine receptor in complex with agonist acetylcholine and positive allosteric modulator VU6007678
Projections & slices

Image control

Size
Brightness
Contrast
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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 300 pix.
= 246. Å		0.82 Å/pix.
x 300 pix.
= 246. Å		0.82 Å/pix.
x 300 pix.
= 246. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.45
Minimum - Maximum-1.0735337 - 2.4283807
Average (Standard dev.)-0.00088294025 (±0.04717081)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 246.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_48108_msk_1.map
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Additional map: aligned to consensus map

Fileemd_48108_additional_1.map
Annotationaligned to consensus map
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Half map: Half Map A

Fileemd_48108_half_map_1.map
AnnotationHalf Map A
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Half map: Half Map B

Fileemd_48108_half_map_2.map
AnnotationHalf Map B
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Sample components

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Entire : Human M5-miniGq-Gb1g2 complex

EntireName: Human M5-miniGq-Gb1g2 complex
Components
  • Complex: Human M5-miniGq-Gb1g2 complex

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Supramolecule #1: Human M5-miniGq-Gb1g2 complex

SupramoleculeName: Human M5-miniGq-Gb1g2 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: Ab initio model
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.11 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 418794
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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