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- PDB-6n4b: Cannabinoid Receptor 1-G Protein Complex -

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Basic information

Entry
Database: PDB / ID: 6n4b
TitleCannabinoid Receptor 1-G Protein Complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Cannabinoid receptor 1Cannabinoid receptor type 1
  • scFv16
KeywordsSIGNALING PROTEIN / Cannabinoid receptor / GPCR / synthetic cannabinoid / Fubinaca / Gi
Function / homology
Function and homology information


regulation of penile erection / induction of synaptic vesicle exocytosis by positive regulation of presynaptic cytosolic calcium ion concentration / cannabinoid receptor activity / cannabinoid signaling pathway / negative regulation of dopamine secretion / negative regulation of mast cell activation / regulation of feeding behavior / regulation of metabolic process / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of nitric-oxide synthase activity ...regulation of penile erection / induction of synaptic vesicle exocytosis by positive regulation of presynaptic cytosolic calcium ion concentration / cannabinoid receptor activity / cannabinoid signaling pathway / negative regulation of dopamine secretion / negative regulation of mast cell activation / regulation of feeding behavior / regulation of metabolic process / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of nitric-oxide synthase activity / negative regulation of fatty acid beta-oxidation / positive regulation of acute inflammatory response to antigenic stimulus / negative regulation of serotonin secretion / negative regulation of action potential / G protein-coupled serotonin receptor binding / positive regulation of protein localization to cell cortex / positive regulation of blood pressure / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of fever generation / cardiac muscle cell apoptotic process / sensory perception of taste / cell cortex region / regulation of cAMP-mediated signaling / G-protein beta/gamma-subunit complex / cellular response to catecholamine stimulus / G-protein gamma-subunit binding / G protein-coupled acetylcholine receptor signaling pathway / alkylglycerophosphoethanolamine phosphodiesterase activity / rhodopsin mediated signaling pathway / regulation of mitotic spindle organization / regulation of synaptic transmission, GABAergic / axonal fasciculation / adenylate cyclase-activating dopamine receptor signaling pathway / photoreceptor outer segment membrane / G-protein beta-subunit binding / cellular response to forskolin / negative regulation of synaptic transmission / photoreceptor disc membrane / spectrin binding / G-protein beta/gamma-subunit complex binding / heterotrimeric G-protein complex / GTPase activating protein binding / maternal process involved in female pregnancy / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to morphine / Wnt signaling pathway, calcium modulating pathway / G protein-coupled receptor activity / extracellular vesicle / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / cellular response to prostaglandin E stimulus / phospholipase C-activating G protein-coupled receptor signaling pathway / regulation of synaptic transmission, glutamatergic / adenylate cyclase-activating G protein-coupled receptor signaling pathway / response to cocaine / regulation of insulin secretion / GTPase binding / response to peptide hormone / retina development in camera-type eye / G protein-coupled receptor binding / negative regulation of blood pressure / sensory perception of pain / photoreceptor inner segment / response to nicotine / positive regulation of neuron projection development / response to nutrient / memory / presynaptic membrane / GDP binding / cell population proliferation / cell body / midbody / growth cone / lysosomal membrane / actin cytoskeleton / glucose homeostasis / cellular response to hypoxia / positive regulation of cytosolic calcium ion concentration / spermatogenesis / platelet activation / Ras protein signal transduction / drug binding / mitochondrial outer membrane / protein folding / response to lipopolysaccharide / response to ethanol / aging / cell cycle / GTPase activity / cell division / centrosome / G protein-coupled receptor signaling pathway / synapse / membrane raft / positive regulation of apoptotic process / GTP binding / dendrite / protein-containing complex binding / signal transduction / magnesium ion binding / integral component of plasma membrane
WD domain, G-beta repeat / WD40 repeat, conserved site / WD40 repeat / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein, gamma subunit / Cannabinoid receptor family / Cannabinoid receptor type 1 / G protein-coupled receptor, rhodopsin-like / G protein alpha subunit, helical insertion / G-protein gamma-like domain ...WD domain, G-beta repeat / WD40 repeat, conserved site / WD40 repeat / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein, gamma subunit / Cannabinoid receptor family / Cannabinoid receptor type 1 / G protein-coupled receptor, rhodopsin-like / G protein alpha subunit, helical insertion / G-protein gamma-like domain / WD40/YVTN repeat-like-containing domain superfamily / Guanine nucleotide-binding protein, beta subunit / G-protein alpha subunit, group I / WD40-repeat-containing domain / GPCR, rhodopsin-like, 7TM / G-protein, beta subunit / G-protein beta WD-40 repeat / P-loop containing nucleoside triphosphate hydrolase / G-protein gamma-like domain superfamily / WD40-repeat-containing domain superfamily / GGL domain / G-protein alpha subunit / 7 transmembrane receptor (rhodopsin family) / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Rhodopsin 7-helix transmembrane proteins / Rhopdopsin 7-helix transmembrane proteins / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Irregular / Few Secondary Structures / P-loop containing nucleotide triphosphate hydrolases / Immunoglobulins / Immunoglobulin-like / Up-down Bundle / Sandwich / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Cannabinoid receptor 1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsKrishna Kumar, K. / Shalev-Benami, M. / Hu, H. / Weis, W.I. / Kobilka, B.K. / Skiniotis, G.
Funding support United States, 2items
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 Report
SummaryFull reportAbout validation report
History
DepositionNov 18, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 30, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 6, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.year
Revision 1.2Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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Structure visualization

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Cannabinoid receptor 1
S: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,5818
Polymers169,4115
Non-polymers1,1713
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area11040 Å2
ΔGint-78 kcal/mol
Surface area51640 Å2

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABC

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40415.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37671.102 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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Protein / Antibody , 2 types, 2 molecules RS

#4: Protein Cannabinoid receptor 1 / Cannabinoid receptor type 1 / CB1 / CANN6


Mass: 55678.535 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CNR1, CNR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P21554
#5: Antibody scFv16


Mass: 27784.896 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Trichoplusia ni (cabbage looper)

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Non-polymers , 2 types, 3 molecules

#6: Chemical ChemComp-KCA / methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}-3-methyl-L-valinate / MDMB-FUBINACA


Mass: 397.443 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24FN3O3 / Comment: agonist*YM
#7: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cannabinoid Receptor 1-G Protein Complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
EM software
IDNameCategory
7UCSF Chimeramodel fitting
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 177787 / Symmetry type: POINT
RefinementHighest resolution: 3 Å
Refine LS restraints
Refinement-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0238638
ELECTRON MICROSCOPYf_angle_d1.38811750
ELECTRON MICROSCOPYf_dihedral_angle_d12.535040
ELECTRON MICROSCOPYf_chiral_restr0.1341371
ELECTRON MICROSCOPYf_plane_restr0.0081463

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