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- EMDB-32850: Allosteric modulator ZCZ011 binding to CP55940-bound cannabinoid ... -
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Open data
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Basic information
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Title | Allosteric modulator ZCZ011 binding to CP55940-bound cannabinoid receptor 1 in complex with Gi protein | |||||||||
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![]() | Complex / agonist / membrane protein | |||||||||
Function / homology | ![]() negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / 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 ...negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / 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 / negative regulation of serotonin secretion / regulation of presynaptic cytosolic calcium ion concentration / G protein-coupled adenosine receptor signaling pathway / negative regulation of action potential / negative regulation of calcium ion-dependent exocytosis / Class A/1 (Rhodopsin-like receptors) / positive regulation of urine volume / negative regulation of adenylate cyclase activity / positive regulation of blood pressure / positive regulation of fever generation / regulation of metabolic process / positive regulation of neural precursor cell proliferation / gamma-aminobutyric acid signaling pathway / axonal fasciculation / negative regulation of synaptic transmission / regulation of synaptic transmission, GABAergic / neuronal dense core vesicle / regulation of calcium ion transport / regulation of insulin secretion / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / negative regulation of apoptotic signaling pathway / GABA-ergic synapse / Adenylate cyclase inhibitory pathway / maternal process involved in female pregnancy / positive regulation of insulin receptor signaling pathway / regulation of synaptic transmission, glutamatergic / positive regulation of vascular associated smooth muscle cell proliferation / negative regulation of blood pressure / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to nutrient / positive regulation of superoxide anion generation / response to cocaine / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / response to nicotine / 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 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 / memory / 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 / positive regulation of neuron projection development / 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 / 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 / actin cytoskeleton / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / glucose homeostasis / retina development in camera-type eye / presynaptic membrane / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / midbody / cell body / growth cone Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.36 Å | |||||||||
![]() | Xu Z / Shao Z | |||||||||
Funding support | 1 items
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![]() | ![]() Title: Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1. Authors: Xin Yang / Xuehui Wang / Zheng Xu / Chao Wu / Yangli Zhou / Yifei Wang / Guifeng Lin / Kan Li / Ming Wu / Anjie Xia / Jingming Liu / Lin Cheng / Jun Zou / Wei Yan / Zhenhua Shao / Shengyong Yang / ![]() Abstract: Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we ...Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we report the crystallographic and cryo-electron microscopy structures of the cannabinoid receptor CB1 bound to the positive allosteric modulator (PAM) ZCZ011. These structures show that ZCZ011 binds to an extrahelical site in the transmembrane 2 (TM2)-TM3-TM4 surface. Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement is critical for the propagation of allosteric signals. ZCZ011 exerts a PAM effect by promoting TM2 rearrangement in favor of receptor activation and increasing the population of receptors that adopt an active conformation. In contrast, ORG27569, a negative allosteric modulator (NAM) of CB1, also binds to the TM2-TM3-TM4 surface and exerts a NAM effect by impeding the TM2 rearrangement. Our findings fill a gap in the understanding of CB1 allosteric regulation and could guide the rational design of CB1 allosteric modulators. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 17.1 KB 17.1 KB | Display Display | ![]() |
Images | ![]() | 34.8 KB | ||
Filedesc metadata | ![]() | 6.6 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 485.6 KB | Display | ![]() |
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Full document | ![]() | 485.2 KB | Display | |
Data in XML | ![]() | 6.2 KB | Display | |
Data in CIF | ![]() | 7.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7wv9MC ![]() 7feeC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.85 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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Sample components
+Entire : Cannabinoid receptor 1 complexed with Gi heterotrimer proteins
+Supramolecule #1: Cannabinoid receptor 1 complexed with Gi heterotrimer proteins
+Supramolecule #2: Cannabinoid receptor 1 complexed with Gi heterotrimer proteins
+Supramolecule #3: ScFv16
+Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-2
+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: 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methy...
+Macromolecule #7: 6-methyl-3-[(1S)-2-nitro-1-thiophen-2-yl-ethyl]-2-phenyl-1H-indole
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 61.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.2 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 358465 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |