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- PDB-8k8j: Cannabinoid Receptor 1 bound to Fenofibrate coupling MiniGsq and ... -

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Basic information

Entry
Database: PDB / ID: 8k8j
TitleCannabinoid Receptor 1 bound to Fenofibrate coupling MiniGsq and Nb35 Complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Nanobody 35Single-domain antibody
  • Soluble cytochrome b562,Cannabinoid receptor 1
KeywordsMEMBRANE PROTEIN / GPCR
Function / homology
Function and homology information


cannabinoid signaling pathway / regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of fatty acid beta-oxidation / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus / regulation of feeding behavior ...cannabinoid signaling pathway / regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of fatty acid beta-oxidation / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus / regulation of feeding behavior / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of serotonin secretion / negative regulation of action potential / Class A/1 (Rhodopsin-like receptors) / positive regulation of blood pressure / positive regulation of fever generation / regulation of metabolic process / axonal fasciculation / regulation of synaptic transmission, GABAergic / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / PKA activation in glucagon signalling / regulation of insulin secretion / hair follicle placode formation / intracellular transport / D1 dopamine receptor binding / GABA-ergic synapse / developmental growth / maternal process involved in female pregnancy / Hedgehog 'off' state / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of synaptic transmission, glutamatergic / activation of adenylate cyclase activity / adenylate cyclase activator activity / negative regulation of blood pressure / response to nutrient / trans-Golgi network membrane / response to cocaine / response to nicotine / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / bone development / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of neuron projection development / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / memory / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / platelet aggregation / Glucagon-type ligand receptors / cognition / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of GTPase activity / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / signaling receptor complex adaptor activity / sensory perception of smell / actin cytoskeleton / Thrombin signalling through proteinase activated receptors (PARs) / glucose homeostasis / retina development in camera-type eye / GTPase binding / presynaptic membrane / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / growth cone / fibroblast proliferation / G alpha (s) signalling events
Similarity search - Function
Cannabinoid receptor type 1 / Cannabinoid receptor family / Cytochrome b562 / Cytochrome b562 / G-protein alpha subunit, group S / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion ...Cannabinoid receptor type 1 / Cannabinoid receptor family / Cytochrome b562 / Cytochrome b562 / G-protein alpha subunit, group S / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / Soluble cytochrome b562 / 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(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsTang, W.Q. / Wang, T.X. / Li, F.H. / Wang, J.Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Adv Sci (Weinh) / Year: 2024
Title: Fenofibrate Recognition and G Protein Coupling Mechanisms of the Human Cannabinoid Receptor CB1.
Authors: Tianxin Wang / Wenqin Tang / Ziyi Zhao / Ran Zhao / Zhenyu Lv / Xuzhen Guo / Quanchang Gu / Boxiang Liu / Haoyu Lv / Jiayan Chen / Kaiquan Zhang / Fahui Li / Jiangyun Wang /
Abstract: The G-protein-coupled human cannabinoid receptor 1 (CB1) is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. The structures of CB1-G complexes ...The G-protein-coupled human cannabinoid receptor 1 (CB1) is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. The structures of CB1-G complexes in synthetic agonist-bound forms have been resolved to date. However, the commercial drug recognition and G coupling mechanisms of CB1 remain elusive. Herein, the cryo-electron microscopy (cryo-EM) structure of CB1-G complex, in fenofibrate-bound form, at near-atomic resolution, is reported. The structure elucidates the delicate mechanisms of the precise fenofibrate recognition and G protein coupling by CB1 and will facilitate future drug discovery and design.
History
DepositionJul 30, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 14, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2024Group: Database references / Category: citation / Item: _citation.journal_volume

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nanobody 35
R: Soluble cytochrome b562,Cannabinoid receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)153,8866
Polymers153,5255
Non-polymers3611
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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

#1: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 30652.561 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Escherichia coli (E. coli) / References: UniProt: P63092
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 10497.960 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody / Protein / Non-polymers , 3 types, 3 molecules NR

#4: Antibody Nanobody 35 / Single-domain antibody


Mass: 15271.938 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Protein Soluble cytochrome b562,Cannabinoid receptor 1 / Cytochrome b-562 / CB-R / CB1 / CANN6


Mass: 59685.355 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: cybC, CNR1, CNR / Production host: Homo sapiens (human) / References: UniProt: P0ABE7, UniProt: P21554
#6: Chemical ChemComp-J3O / propan-2-yl 2-[4-(4-chlorophenyl)carbonylphenoxy]-2-methyl-propanoate


Mass: 360.831 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21ClO4 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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: #5, #1-#4 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen 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 / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 352452 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0088292
ELECTRON MICROSCOPYf_angle_d0.97211227
ELECTRON MICROSCOPYf_dihedral_angle_d4.4521127
ELECTRON MICROSCOPYf_chiral_restr0.0431277
ELECTRON MICROSCOPYf_plane_restr0.0041423

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