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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 1
  • scFv16
KeywordsSIGNALING PROTEIN / Cannabinoid receptor / GPCR / synthetic cannabinoid / Fubinaca / Gi
Function / homologyGlucagon-type ligand receptors / GPCR, rhodopsin-like, 7TM / G-protein gamma subunit domain profile. / Trp-Asp (WD) repeats signature. / G-protein coupled receptors family 1 signature. / GGL domain / Vasopressin regulates renal water homeostasis via Aquaporins / WD domain, G-beta repeat / 7 transmembrane receptor (rhodopsin family) / WD40-repeat-containing domain superfamily ...Glucagon-type ligand receptors / GPCR, rhodopsin-like, 7TM / G-protein gamma subunit domain profile. / Trp-Asp (WD) repeats signature. / G-protein coupled receptors family 1 signature. / GGL domain / Vasopressin regulates renal water homeostasis via Aquaporins / WD domain, G-beta repeat / 7 transmembrane receptor (rhodopsin family) / WD40-repeat-containing domain superfamily / G-protein gamma-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase / G-protein beta WD-40 repeat / WD40 repeat, conserved site / WD40-repeat-containing domain / Guanine nucleotide-binding protein, beta subunit / G-protein coupled receptors family 1 profile. / WD40/YVTN repeat-like-containing domain superfamily / G-protein gamma-like domain / G protein alpha subunit, helical insertion / Cannabinoid receptor family / G-protein, gamma subunit / WD40 repeat / G-protein, beta subunit / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / Cannabinoid receptor type 1 / G protein-coupled receptor, rhodopsin-like / Thromboxane signalling through TP receptor / Regulation of insulin secretion / Trp-Asp (WD) repeats profile. / G-protein alpha subunit / Trp-Asp (WD) repeats circular profile. / G beta:gamma signalling through PI3Kgamma / G alpha (q) signalling events / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / PLC beta mediated events / G alpha (s) signalling events / Presynaptic function of Kainate receptors / Ca2+ pathway / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / ADP signalling through P2Y purinoceptor 1 / Thrombin signalling through proteinase activated receptors (PARs) / Adrenaline,noradrenaline inhibits insulin secretion / Prostacyclin signalling through prostacyclin receptor / ADP signalling through P2Y purinoceptor 12 / G alpha (12/13) signalling events / Olfactory Signaling Pathway / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Class A/1 (Rhodopsin-like receptors) / Inactivation, recovery and regulation of the phototransduction cascade / Activation of the phototransduction cascade / G alpha (i) signalling events / G-protein activation / Adenylate cyclase inhibitory pathway / G alpha (z) signalling events / Glucagon signaling in metabolic regulation / Activation of G protein gated Potassium channels / G beta:gamma signalling through PLC beta / retrograde trans-synaptic signaling by endocannabinoid / regulation of penile erection / cannabinoid signaling pathway / cannabinoid receptor activity / negative regulation of dopamine secretion / voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels / negative regulation of mast cell activation / regulation of feeding behavior / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of nitric-oxide synthase activity / negative regulation of fatty acid beta-oxidation / negative regulation of action potential / cellular response to catecholamine stimulus / regulation of cAMP-mediated signaling / integral component of mitochondrial membrane / G protein-coupled serotonin receptor binding / cardiac muscle cell apoptotic process / positive regulation of acute inflammatory response to antigenic stimulus / positive regulation of protein localization to cell cortex / G protein-coupled acetylcholine receptor signaling pathway / protein heterotrimerization / sensory perception of taste / alkylglycerophosphoethanolamine phosphodiesterase activity / G-protein beta-subunit binding / adenylate cyclase-activating dopamine receptor signaling pathway / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / rhodopsin mediated signaling pathway / photoreceptor outer segment membrane / cell cortex region / positive regulation of blood pressure / positive regulation of fever generation / G-protein beta/gamma-subunit complex binding / spectrin binding / photoreceptor disc membrane / regulation of synaptic transmission, GABAergic / regulation of mitotic spindle organization / heterotrimeric G-protein complex / cellular response to forskolin / Wnt signaling pathway, calcium modulating pathway / axonal fasciculation / GABA-ergic synapse
Function and homology information
Specimen sourceHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 3 Å resolution
AuthorsKrishna Kumar, K. / Shalev-Benami, M. / Hu, H. / Weis, W.I. / Kobilka, B.K. / Skiniotis, G.
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 / 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
DateDeposition: Nov 18, 2018 / Release: Jan 30, 2019
RevisionDateData content typeGroupCategoryItemProviderType
1.0Jan 30, 2019Structure modelrepositoryInitial release
1.1Feb 6, 2019Structure modelData collection / Database referencescitation_citation.journal_volume / _citation.page_first / _citation.year

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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
Polyers169,4115
Non-polymers1,1713
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)11040
ΔGint (kcal/M)-78
Surface area (Å2)51640

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Components

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

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


Mass: 40415.031 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63096
#2: Protein/peptide 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: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#3: Protein/peptide 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: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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Protein/peptide , 2 types, 2 molecules RS

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


Mass: 55678.535 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Gene: CNR1, CNR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P21554
#5: Protein/peptide scFv16


Mass: 27784.896 Da / Num. of mol.: 1 / 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


Mass: 397.443 Da / Num. of mol.: 1 / Formula: C22H24FN3O3
#7: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Formula: C27H46O / Cholesterol

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Cannabinoid Receptor 1-G Protein Complex / Type: COMPLEX / Entity ID: 1, 2, 3, 4, 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 / 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
MicroscopyMicroscope model: 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
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 177787 / Symmetry type: POINT
Least-squares processHighest resolution: 3 Å
Refine LS restraints
Refine IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0238638
ELECTRON MICROSCOPYf_angle_d1.38811750
ELECTRON MICROSCOPYf_dihedral_angle_d12.5305040
ELECTRON MICROSCOPYf_chiral_restr0.1341371
ELECTRON MICROSCOPYf_plane_restr0.0081463

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