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Open data
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Basic information
Entry | Database: PDB / ID: 8k9k | |||||||||||||||
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Title | Full agonist-bound mu-type opioid receptor-G protein complex | |||||||||||||||
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![]() | SIGNALING PROTEIN | |||||||||||||||
Function / homology | ![]() Opioid Signalling / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / regulation of cellular response to stress / G protein-coupled opioid receptor signaling pathway / behavioral response to ethanol / positive regulation of cAMP-mediated signaling / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / sensory perception ...Opioid Signalling / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / regulation of cellular response to stress / G protein-coupled opioid receptor signaling pathway / behavioral response to ethanol / positive regulation of cAMP-mediated signaling / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / sensory perception / negative regulation of nitric oxide biosynthetic process / neuropeptide binding / negative regulation of cAMP-mediated signaling / GTP metabolic process / regulation of NMDA receptor activity / positive regulation of neurogenesis / G protein-coupled dopamine receptor signaling pathway / negative regulation of cytosolic calcium ion concentration / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of macroautophagy / G-protein alpha-subunit binding / voltage-gated calcium channel activity / neuropeptide signaling pathway / MECP2 regulates neuronal receptors and channels / sensory perception of pain / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / G protein-coupled receptor binding / G protein-coupled receptor activity / electron transport chain / G-protein beta/gamma-subunit complex binding / 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 / 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 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / 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 / 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 / heterotrimeric G-protein complex / positive regulation of nitric oxide biosynthetic process / G alpha (12/13) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / midbody / G alpha (i) signalling events / positive regulation of cytosolic calcium ion concentration / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / perikaryon / Interleukin-4 and Interleukin-13 signaling / Extra-nuclear estrogen signaling / periplasmic space / electron transfer activity / positive regulation of ERK1 and ERK2 cascade / endosome / neuron projection / iron ion binding / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / cell division / axon / Golgi membrane / GTPase activity / centrosome / synapse / dendrite / heme binding / endoplasmic reticulum membrane / nucleolus / GTP binding / Golgi apparatus / endoplasmic reticulum / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytoplasm Similarity search - Function | |||||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() synthetic construct (others) | |||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.98 Å | |||||||||||||||
![]() | Hisano, T. / Uchikubo-Kamo, T. / Shirouzu, M. / Imai, S. / Kaneko, S. / Shimada, I. | |||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator. Authors: Shun Kaneko / Shunsuke Imai / Tomomi Uchikubo-Kamo / Tamao Hisano / Nobuaki Asao / Mikako Shirouzu / Ichio Shimada / ![]() Abstract: G-protein-coupled receptors (GPCRs) play pivotal roles in various physiological processes. These receptors are activated to different extents by diverse orthosteric ligands and allosteric modulators. ...G-protein-coupled receptors (GPCRs) play pivotal roles in various physiological processes. These receptors are activated to different extents by diverse orthosteric ligands and allosteric modulators. However, the mechanisms underlying these variations in signaling activity by allosteric modulators remain largely elusive. Here, we determine the three-dimensional structure of the μ-opioid receptor (MOR), a class A GPCR, in complex with the G protein and an allosteric modulator, BMS-986122, using cryogenic electron microscopy. Our results reveal that BMS-986122 binding induces changes in the map densities corresponding to R167 and Y254, key residues in the structural motifs conserved among class A GPCRs. Nuclear magnetic resonance analyses of MOR in the absence of the G protein reveal that BMS-986122 binding enhances the formation of the interaction between R167 and Y254, thus stabilizing the fully-activated conformation, where the intracellular half of TM6 is outward-shifted to allow for interaction with the G protein. These findings illuminate that allosteric modulators like BMS-986122 can potentiate receptor activation through alterations in the conformational dynamics in the core region of GPCRs. Together, our results demonstrate the regulatory mechanisms of GPCRs, providing insights into the rational development of therapeutics targeting GPCRs. | |||||||||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 244.4 KB | Display | ![]() |
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PDB format | ![]() | 186.9 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.2 MB | Display | ![]() |
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Full document | ![]() | 1.2 MB | Display | |
Data in XML | ![]() | 45.6 KB | Display | |
Data in CIF | ![]() | 69.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 36989MC ![]() 8k9lC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Components
-Protein , 4 types, 4 molecules RABG
#1: Protein | Mass: 51321.855 Da / Num. of mol.: 1 / Mutation: M7W,H102I,R106L Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() Gene: cybC, OPRM1, MOR1 / Production host: ![]() ![]() |
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#3: Protein | Mass: 40585.137 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() |
#4: Protein | Mass: 38522.098 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#5: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
-Protein/peptide / Antibody , 2 types, 2 molecules SH
#2: Protein/peptide | |
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#6: Antibody | Mass: 27409.588 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) synthetic construct (others) / Production host: ![]() ![]() |
-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 |
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Sample preparation
Component | Name: Full agonist-bound mu-type opioid receptor-G protein complex Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Units: MEGADALTONS / Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 2.3 sec. / Electron dose: 50.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
EM imaging optics | Energyfilter name: GIF Quantum LS / Energyfilter slit width: 15 eV |
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Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 308249 / Symmetry type: POINT | ||||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT / Space: REAL | ||||||||||||||||||||||||||||
Refine LS restraints |
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