+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-35512 | |||||||||
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Title | Cryo-EM structure of human receptor with G proteins | |||||||||
Map data | ||||||||||
Sample |
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Keywords | MEMBRANE PROTEIN / complex / allosteric modulator | |||||||||
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 / regulation of feeding behavior / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus ...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 / regulation of feeding behavior / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus / negative regulation of serotonin secretion / regulation of presynaptic cytosolic calcium ion concentration / 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 / regulation of insulin secretion / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / maternal process involved in female pregnancy / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / GABA-ergic synapse / regulation of mitotic spindle organization / regulation of synaptic transmission, glutamatergic / negative regulation of blood pressure / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / response to nutrient / response to cocaine / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / response to nicotine / adenylate cyclase-activating G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / 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 / G beta:gamma signalling through CDC42 / memory / positive regulation of neuron projection development / response to peptide hormone / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GDP binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / actin cytoskeleton / signaling receptor complex adaptor activity / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / glucose homeostasis / retina development in camera-type eye / presynaptic membrane / Ca2+ pathway / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / midbody / growth cone / fibroblast proliferation / spermatogenesis / G alpha (s) signalling events Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
Authors | Shen SY / Shao ZH / Yan W | |||||||||
Funding support | China, 1 items
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Citation | Journal: Proc Natl Acad Sci U S A / Year: 2024 Title: Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1. Authors: Siyuan Shen / Chao Wu / Guifeng Lin / Xin Yang / Yangli Zhou / Chang Zhao / Zhuang Miao / Xiaowen Tian / Kexin Wang / Zhiqian Yang / Zhiyu Liu / Nihong Guo / Yueshan Li / Anjie Xia / Pei ...Authors: Siyuan Shen / Chao Wu / Guifeng Lin / Xin Yang / Yangli Zhou / Chang Zhao / Zhuang Miao / Xiaowen Tian / Kexin Wang / Zhiqian Yang / Zhiyu Liu / Nihong Guo / Yueshan Li / Anjie Xia / Pei Zhou / Jingming Liu / Wei Yan / Bowen Ke / Shengyong Yang / Zhenhua Shao / Abstract: is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other ... is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and β-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_35512.map.gz | 59.7 MB | EMDB map data format | |
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Header (meta data) | emd-35512-v30.xml emd-35512.xml | 21.3 KB 21.3 KB | Display Display | EMDB header |
Images | emd_35512.png | 165.5 KB | ||
Filedesc metadata | emd-35512.cif.gz | 6.6 KB | ||
Others | emd_35512_half_map_1.map.gz emd_35512_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-35512 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-35512 | HTTPS FTP |
-Validation report
Summary document | emd_35512_validation.pdf.gz | 815.4 KB | Display | EMDB validaton report |
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Full document | emd_35512_full_validation.pdf.gz | 814.9 KB | Display | |
Data in XML | emd_35512_validation.xml.gz | 12.3 KB | Display | |
Data in CIF | emd_35512_validation.cif.gz | 14.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-35512 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-35512 | HTTPS FTP |
-Related structure data
Related structure data | 8ikhMC 8ikgC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_35512.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.89 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_35512_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_35512_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : CB05-bound CB1R in complex with Gi heterotrimer
+Supramolecule #1: CB05-bound CB1R in complex with Gi heterotrimer
+Supramolecule #2: Gi heterotrimer
+Supramolecule #3: scFV16
+Supramolecule #4: Cannabinoid receptor 1
+Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #4: Cannabinoid receptor 1
+Macromolecule #5: scFV16
+Macromolecule #6: 3-[(1R)-1-(2-methoxyphenyl)-2-nitro-ethyl]-2-phenyl-1H-indole
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 65.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 0.01 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 251705 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |