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- EMDB-0339: Cannabinoid Receptor 1-G Protein Complex -

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Basic information

Entry
Database: EMDB / ID: EMD-0339
TitleCannabinoid Receptor 1-G Protein Complex
Map data
SampleCannabinoid Receptor 1-G Protein Complex
  • (Guanine nucleotide-binding protein ...) x 3
  • Cannabinoid receptor 1Cannabinoid receptor type 1
  • scFv16
  • (ligand) x 2
Function / homology
Function and homology information


regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid signaling pathway / cannabinoid receptor activity / negative regulation of dopamine secretion / regulation of feeding behavior / negative regulation of mast cell activation / voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of nitric-oxide synthase activity ...regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid signaling pathway / cannabinoid receptor activity / negative regulation of dopamine secretion / regulation of feeding behavior / negative regulation of mast cell activation / voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of nitric-oxide synthase activity / negative regulation of fatty acid beta-oxidation / integral component of mitochondrial membrane / positive regulation of acute inflammatory response to antigenic stimulus / negative regulation of action potential / G protein-coupled serotonin receptor binding / cardiac muscle cell apoptotic process / regulation of cAMP-mediated signaling / positive regulation of protein localization to cell cortex / sensory perception of taste / G-protein beta/gamma-subunit complex / cellular response to catecholamine stimulus / G protein-coupled acetylcholine receptor signaling pathway / alkylglycerophosphoethanolamine phosphodiesterase activity / positive regulation of blood pressure / positive regulation of fever generation / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / cell cortex region / rhodopsin mediated signaling pathway / adenylate cyclase-activating dopamine receptor signaling pathway / G-protein beta-subunit binding / photoreceptor outer segment membrane / photoreceptor disc membrane / regulation of synaptic transmission, GABAergic / regulation of mitotic spindle organization / spectrin binding / negative regulation of synaptic transmission / G-protein beta/gamma-subunit complex binding / cellular response to forskolin / heterotrimeric G-protein complex / axonal fasciculation / GABA-ergic synapse / GTPase activating protein binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / maternal process involved in female pregnancy / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / extracellular vesicle / Wnt signaling pathway, calcium modulating pathway / cellular response to prostaglandin E stimulus / response to morphine / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / response to cocaine / regulation of insulin secretion / regulation of synaptic transmission, glutamatergic / GTPase binding / response to peptide hormone / sensory perception of pain / photoreceptor inner segment / G protein-coupled receptor binding / negative regulation of blood pressure / response to nicotine / positive regulation of neuron projection development / integral component of presynaptic membrane / response to nutrient / memory / GDP binding / cell body / midbody / actin cytoskeleton / growth cone / lysosomal membrane / cellular response to hypoxia / positive regulation of cytosolic calcium ion concentration / glucose homeostasis / spermatogenesis / platelet activation / Ras protein signal transduction / cell population proliferation / drug binding / protein folding / mitochondrial outer membrane / response to lipopolysaccharide / response to ethanol / aging / cell cycle / GTPase activity / centrosome / cell division / synapse / protein-containing complex binding / G protein-coupled receptor signaling pathway / cell junction / membrane raft / positive regulation of apoptotic process / glutamatergic synapse / GTP binding / dendrite / signal transduction / integral component of plasma membrane / magnesium ion binding
G-protein gamma-like domain / G-protein alpha subunit, group I / GPCR, rhodopsin-like, 7TM / WD40-repeat-containing domain / Guanine nucleotide-binding protein, beta subunit / G protein-coupled receptor, rhodopsin-like / Cannabinoid receptor type 1 / Guanine nucleotide binding protein (G-protein), alpha subunit / WD40 repeat, conserved site / G-protein beta WD-40 repeat ...G-protein gamma-like domain / G-protein alpha subunit, group I / GPCR, rhodopsin-like, 7TM / WD40-repeat-containing domain / Guanine nucleotide-binding protein, beta subunit / G protein-coupled receptor, rhodopsin-like / Cannabinoid receptor type 1 / Guanine nucleotide binding protein (G-protein), alpha subunit / WD40 repeat, conserved site / G-protein beta WD-40 repeat / WD40/YVTN repeat-like-containing domain superfamily / G-protein, beta subunit / G protein alpha subunit, helical insertion / P-loop containing nucleoside triphosphate hydrolase / WD40 repeat / G-protein gamma-like domain superfamily / WD40-repeat-containing domain superfamily / G-protein, gamma subunit / Cannabinoid receptor family
Cannabinoid receptor 1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsKrishna Kumar K / Shalev-Benami M / Hu H / Weis WI / Kobilka BK / Skiniotis G
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)R37DA036246 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)R01GM083118 United States
CitationJournal: Cell / Year: 2019
Title: Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex.
Authors: Kaavya Krishna Kumar / Moran Shalev-Benami / Michael J Robertson / Hongli Hu / Samuel D Banister / Scott A Hollingsworth / Naomi R Latorraca / Hideaki E Kato / Daniel Hilger / Shoji Maeda / ...Authors: Kaavya Krishna Kumar / Moran Shalev-Benami / Michael J Robertson / Hongli Hu / Samuel D Banister / Scott A Hollingsworth / Naomi R Latorraca / Hideaki E Kato / Daniel Hilger / Shoji Maeda / William I Weis / David L Farrens / Ron O Dror / Sanjay V Malhotra / Brian K Kobilka / Georgios Skiniotis /
Abstract: Cannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting ...Cannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting heterotrimeric G protein G. Activation of CB1-G signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of G activation by CB1. Here, we present the structure of the CB1-G signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities. The structure illustrates how FUB stabilizes the receptor in an active state to facilitate nucleotide exchange in G. The results compose the structural framework to explain CB1 activation by different classes of ligands and provide insights into the G protein coupling and selectivity mechanisms adopted by the receptor.
Validation ReportPDB-ID: 6n4b

SummaryFull reportAbout validation report
History
DepositionNov 18, 2018-
Header (metadata) releaseJan 23, 2019-
Map releaseJan 30, 2019-
UpdateDec 11, 2019-
Current statusDec 11, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.12
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.12
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6n4b
  • Surface level: 0.09
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_0339.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 240 pix.
= 206.4 Å
0.86 Å/pix.
x 240 pix.
= 206.4 Å
0.86 Å/pix.
x 240 pix.
= 206.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density
Contour LevelBy AUTHOR: 0.085 / Movie #1: 0.12
Minimum - Maximum-0.5023643 - 0.91575676
Average (Standard dev.)-0.0012226657 (±0.029975073)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 206.40001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.860.860.86
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z206.400206.400206.400
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.5020.916-0.001

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Supplemental data

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Sample components

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Entire Cannabinoid Receptor 1-G Protein Complex

EntireName: Cannabinoid Receptor 1-G Protein Complex / Number of components: 8

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Component #1: protein, Cannabinoid Receptor 1-G Protein Complex

ProteinName: Cannabinoid Receptor 1-G Protein Complex / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #2: protein, Guanine nucleotide-binding protein G(i) subunit alpha-1

ProteinName: Guanine nucleotide-binding protein G(i) subunit alpha-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 40.415031 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #3: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 37.671102 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #4: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 7.861143 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #5: protein, Cannabinoid receptor 1

ProteinName: Cannabinoid receptor 1Cannabinoid receptor type 1 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 55.678535 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #6: protein, scFv16

ProteinName: scFv16 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 27.784896 kDa
SourceSpecies: Mus musculus (house mouse)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #7: ligand, methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbon...

LigandName: methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}-3-methyl-L-valinate
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.397443 kDa

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Component #8: ligand, CHOLESTEROL

LigandName: CHOLESTEROL / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 0.386654 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 5 mg/mL / pH: 7.5
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 50 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 177787
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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