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- EMDB-40057: Cannabinoid Receptor 1/G protein complex, Global Refinement -

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Basic information

Entry
Database: EMDB / ID: EMD-40057
TitleCannabinoid Receptor 1/G protein complex, Global Refinement
Map data
Sample
  • Complex: Cannabinoid Receptor 1 in complex with Gi protein heterotrimer and scFv16
    • Complex: Cannabinoid Receptor 1
    • Complex: Gi G protein heterotrimer
    • Complex: scFv16
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsKrishna Kumar K / Robertson MJ / Skiniotis G / Kobilka BK
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM127359 United States
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis for activation of CB1 by an endocannabinoid analog.
Authors: Kaavya Krishna Kumar / Michael J Robertson / Elina Thadhani / Haoqing Wang / Carl-Mikael Suomivuori / Alexander S Powers / Lipin Ji / Spyros P Nikas / Ron O Dror / Asuka Inoue / Alexandros ...Authors: Kaavya Krishna Kumar / Michael J Robertson / Elina Thadhani / Haoqing Wang / Carl-Mikael Suomivuori / Alexander S Powers / Lipin Ji / Spyros P Nikas / Ron O Dror / Asuka Inoue / Alexandros Makriyannis / Georgios Skiniotis / Brian Kobilka /
Abstract: Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, ...Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, understanding the structural and functional consequences of eCB-CB1 interactions has important implications for designing effective drugs targeting this receptor. To characterize the molecular details of eCB interaction with CB1, we utilized AMG315, an analog of the eCB anandamide to determine the structure of the AMG315-bound CB1 signaling complex. Compared to previous structures, the ligand binding pocket shows some differences. Using docking, molecular dynamics simulations, and signaling assays we investigated the functional consequences of ligand interactions with the "toggle switch" residues F200 and W356. Further, we show that ligand-TM2 interactions drive changes to residues on the intracellular side of TM2 and are a determinant of efficacy in activating G protein. These intracellular TM2 rearrangements are unique to CB1 and are exploited by a CB1-specific allosteric modulator.
History
DepositionMar 13, 2023-
Header (metadata) releaseMay 24, 2023-
Map releaseMay 24, 2023-
UpdateMay 24, 2023-
Current statusMay 24, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40057.png

Downloads & links

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Map

FileDownload / File: emd_40057.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.8521 Å
Density
Contour LevelBy AUTHOR: 0.333
Minimum - Maximum-2.163889 - 3.2045636
Average (Standard dev.)-0.0011672615 (±0.047297265)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 306.756 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_40057_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_40057_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Cannabinoid Receptor 1 in complex with Gi protein heterotrimer an...

EntireName: Cannabinoid Receptor 1 in complex with Gi protein heterotrimer and scFv16
Components
  • Complex: Cannabinoid Receptor 1 in complex with Gi protein heterotrimer and scFv16
    • Complex: Cannabinoid Receptor 1
    • Complex: Gi G protein heterotrimer
    • Complex: scFv16

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Supramolecule #1: Cannabinoid Receptor 1 in complex with Gi protein heterotrimer an...

SupramoleculeName: Cannabinoid Receptor 1 in complex with Gi protein heterotrimer and scFv16
type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: Cannabinoid Receptor 1

SupramoleculeName: Cannabinoid Receptor 1 / type: complex / ID: 2 / Chimera: Yes / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Gi G protein heterotrimer

SupramoleculeName: Gi G protein heterotrimer / type: complex / ID: 3 / Chimera: Yes / Parent: 1 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: scFv16

SupramoleculeName: scFv16 / type: complex / ID: 4 / Chimera: Yes / Parent: 1 / Macromolecule list: #5
Source (natural)Organism: Mus musculus (house mouse)

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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: 80.09 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 530918
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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