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- EMDB-64557: A cryo_EM structure of Cagrilintide-CTR-Gs complex -

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Basic information

Entry
Database: EMDB / ID: EMD-64557
TitleA cryo_EM structure of Cagrilintide-CTR-Gs complex
Map data
Sample
  • Complex: A cryo_EM structure of Cagrilintide-CTR-Gs complex
KeywordsGPCR / CTR / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.15 Å
Authorszhao L / Gu Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Acta Pharmacol Sin / Year: 2026
Title: Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors.
Authors: Yi-Min Gu / Qing-Ning Yuan / Xin Li / Qian He / H Eric Xu / Li-Hua Zhao /
Abstract: The global obesity epidemic and its associated metabolic disorders urgently require more effective therapeutic interventions, particularly multi-pathway targeting therapies. Cagrilintide (Cagri), ...The global obesity epidemic and its associated metabolic disorders urgently require more effective therapeutic interventions, particularly multi-pathway targeting therapies. Cagrilintide (Cagri), functioning as a dual amylin receptor (AMYRs) and calcitonin receptor (CTR) agonist (DACRA), demonstrates significant efficacy in obesity treatment, although its structural activation mechanism remains unclear. This study elucidates the non-selective activation mechanism by determining cryo-EM structures of Cagri bound to AMYR-G and CTR-G complexes. Cagri adopts similar "bypass" binding modes in both receptors, which is distinct from other existing DACRAs that primarily achieve extended half-life through N-terminal lipid modification. Key molecular features include the F23 residue anchoring the peptide at the receptor transmembrane (TM) bundle level and the micelle, an E14-R17 intramolecular salt bridge enhancing helical stability, and C-terminal P37 interaction with the receptor ECD. These features collectively enable non-specific binding and activation across different receptors. Both structural and functional analyses revealed Cagri's non-selective activation of G signaling pathways through CTR and AMYR. These findings provide a comprehensive structural framework for developing next-generation anti-obesity drugs based on dual receptor activation mechanisms.
History
DepositionMay 12, 2025-
Header (metadata) releaseMay 27, 2026-
Map releaseMay 27, 2026-
UpdateMay 27, 2026-
Current statusMay 27, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_64557.png

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Map

FileDownload / File: emd_64557.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 360 pix.
= 262.8 Å		0.73 Å/pix.
x 360 pix.
= 262.8 Å		0.73 Å/pix.
x 360 pix.
= 262.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.227
Minimum - Maximum-1.2283633 - 2.1228166
Average (Standard dev.)-0.00009974517 (±0.038216207)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 262.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_64557_half_map_1.map
Projections & Slices
AxesZYX

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Half map: #2

Fileemd_64557_half_map_2.map
Projections & Slices
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Sample components

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Entire : A cryo_EM structure of Cagrilintide-CTR-Gs complex

EntireName: A cryo_EM structure of Cagrilintide-CTR-Gs complex
Components
  • Complex: A cryo_EM structure of Cagrilintide-CTR-Gs complex

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Supramolecule #1: A cryo_EM structure of Cagrilintide-CTR-Gs complex

SupramoleculeName: A cryo_EM structure of Cagrilintide-CTR-Gs complex / type: complex / ID: 1 / Parent: 0
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: 7.04
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 18.0 µm / Nominal defocus min: 8.0 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: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.15 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 88108
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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