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Yorodumi- PDB-6pt0: Cryo-EM structure of human cannabinoid receptor 2-Gi protein in c... -
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-Basic information
Entry | Database: PDB / ID: 6pt0 | |||||||||||||||||||||
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Title | Cryo-EM structure of human cannabinoid receptor 2-Gi protein in complex with agonist WIN 55,212-2 | |||||||||||||||||||||
Components |
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Keywords | MEMBRANE PROTEIN / GPCR complex / WIN55 / 212-2 | |||||||||||||||||||||
Function / homology | Function and homology information cannabinoid receptor activity / negative regulation of mast cell activation / negative regulation of synaptic transmission, GABAergic / negative regulation of action potential / Class A/1 (Rhodopsin-like receptors) / regulation of metabolic process / leukocyte chemotaxis / extrinsic component of cytoplasmic side of plasma membrane / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / Adenylate cyclase inhibitory pathway ...cannabinoid receptor activity / negative regulation of mast cell activation / negative regulation of synaptic transmission, GABAergic / negative regulation of action potential / Class A/1 (Rhodopsin-like receptors) / regulation of metabolic process / leukocyte chemotaxis / extrinsic component of cytoplasmic side of plasma membrane / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / response to amphetamine / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / 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 / response to peptide hormone / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / perikaryon / Extra-nuclear estrogen signaling / cell population proliferation / response to lipopolysaccharide / inflammatory response / immune response / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / dendrite / protein-containing complex binding / nucleolus / GTP binding / magnesium ion binding / signal transduction / endoplasmic reticulum / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||||||||||||||
Biological species | Homo sapiens (human) synthetic construct (others) | |||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||||||||||||||
Authors | Xu, T.H. / Xing, C. / Zhuang, Y. / Feng, Z. / Zhou, X.E. / Chen, M. / Wang, L. / Meng, X. / Xue, Y. / Wang, J. ...Xu, T.H. / Xing, C. / Zhuang, Y. / Feng, Z. / Zhou, X.E. / Chen, M. / Wang, L. / Meng, X. / Xue, Y. / Wang, J. / Liu, H. / McGuire, T. / Zhao, G. / Melcher, K. / Zhang, C. / Xu, H.E. / Xie, X.Q. | |||||||||||||||||||||
Funding support | United States, China, 6items
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Citation | Journal: Cell / Year: 2020 Title: Cryo-EM Structure of the Human Cannabinoid Receptor CB2-G Signaling Complex. Authors: Changrui Xing / Youwen Zhuang / Ting-Hai Xu / Zhiwei Feng / X Edward Zhou / Maozi Chen / Lei Wang / Xing Meng / Ying Xue / Junmei Wang / Heng Liu / Terence Francis McGuire / Gongpu Zhao / ...Authors: Changrui Xing / Youwen Zhuang / Ting-Hai Xu / Zhiwei Feng / X Edward Zhou / Maozi Chen / Lei Wang / Xing Meng / Ying Xue / Junmei Wang / Heng Liu / Terence Francis McGuire / Gongpu Zhao / Karsten Melcher / Cheng Zhang / H Eric Xu / Xiang-Qun Xie / Abstract: Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 ...Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 activation and signaling are poorly understood but critical for drug design. Here we report the cryo-EM structure of the human CB2-G signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and G coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system. | |||||||||||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6pt0.cif.gz | 235.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6pt0.ent.gz | 193.4 KB | Display | PDB format |
PDBx/mmJSON format | 6pt0.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6pt0_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 6pt0_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 6pt0_validation.xml.gz | 43.5 KB | Display | |
Data in CIF | 6pt0_validation.cif.gz | 65.9 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/pt/6pt0 ftp://data.pdbj.org/pub/pdb/validation_reports/pt/6pt0 | HTTPS FTP |
-Related structure data
Related structure data | 20470MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABC
#2: Protein | Mass: 40414.047 Da / Num. of mol.: 1 / Mutation: S47N/G203A/E245A/A326S Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096 |
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#3: Protein | Mass: 39151.855 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 |
#4: Protein | Mass: 7563.750 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 |
-Protein / Antibody , 2 types, 2 molecules RE
#1: Protein | Mass: 40764.820 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: CNR2, CB2A, CB2B / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P34972 |
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#5: Antibody | Mass: 27784.896 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli) |
-Non-polymers , 3 types, 9 molecules
#6: Chemical | ChemComp-WI5 / {( | ||
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#7: Chemical | ChemComp-PLM / #8: Chemical | ChemComp-CLR / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: human cannabinoid receptor 2-Gi protein / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT |
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Molecular weight | Units: MEGADALTONS / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.2 |
Specimen | Conc.: 7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES Details: Cryo-EM structure of human cannabinoid receptor 2-Gi protein in complex agonist WIN 55,212-2 |
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Cs: 2.7 mm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Average exposure time: 8 sec. / Electron dose: 2.08 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 8810 |
-Processing
Software | Name: PHENIX / Version: 1.13_2998: / Classification: refinement |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
Particle selection | Num. of particles selected: 1590810 |
3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 721844 / Symmetry type: POINT |