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Yorodumi- PDB-7t2g: CryoEM structure of mu-opioid receptor - Gi protein complex bound... -
+Open data
-Basic information
Entry | Database: PDB / ID: 7t2g | |||||||||
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Title | CryoEM structure of mu-opioid receptor - Gi protein complex bound to mitragynine pseudoindoxyl (MP) | |||||||||
Components |
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Keywords | MEMBRANE PROTEIN / GPCR / mu-opioid receptor / lofentanil (LFT) / mitragynine pseudoindoxyl (MP) | |||||||||
Function / homology | Function and homology information Opioid Signalling / spine apparatus / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / Peptide ligand-binding receptors / adenylate cyclase-inhibiting opioid receptor signaling pathway / positive regulation of appetite / G-protein activation / G protein-coupled opioid receptor activity ...Opioid Signalling / spine apparatus / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / Peptide ligand-binding receptors / adenylate cyclase-inhibiting opioid receptor signaling pathway / positive regulation of appetite / G-protein activation / G protein-coupled opioid receptor activity / filamin binding / G protein-coupled opioid receptor signaling pathway / regulation of cellular response to stress / G alpha (i) signalling events / behavioral response to ethanol / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / negative regulation of nitric oxide biosynthetic process / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / neuropeptide binding / negative regulation of cAMP-mediated signaling / regulation of NMDA receptor activity / positive regulation of neurogenesis / eating behavior / negative regulation of cytosolic calcium ion concentration / transmission of nerve impulse / G-protein alpha-subunit binding / neuropeptide signaling pathway / Adenylate cyclase inhibitory pathway / GABA-ergic synapse / voltage-gated calcium channel activity / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / positive regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / sensory perception of pain / dendrite membrane / presynaptic modulation of chemical synaptic transmission / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / excitatory postsynaptic potential / dendrite cytoplasm / locomotory behavior / Regulation of insulin secretion / electron transport chain / G protein-coupled receptor activity / 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 / 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 / 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 / response to peptide hormone / 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 / GDP binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / positive regulation of nitric oxide biosynthetic process / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / presynaptic membrane / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / cell cortex / midbody / G alpha (i) signalling events / positive regulation of cytosolic calcium ion concentration Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) Escherichia coli (E. coli) Mus musculus (house mouse) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å | |||||||||
Authors | Seven, A.B. / Qu, Q. / Robertson, M.J. / Wang, H. / Kobilka, B.K. / Skiniotis, G. | |||||||||
Funding support | United States, 1items
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Citation | Journal: Nat Chem Biol / Year: 2023 Title: Insights into distinct signaling profiles of the µOR activated by diverse agonists. Authors: Qianhui Qu / Weijiao Huang / Deniz Aydin / Joseph M Paggi / Alpay B Seven / Haoqing Wang / Soumen Chakraborty / Tao Che / Jeffrey F DiBerto / Michael J Robertson / Asuka Inoue / Carl-Mikael ...Authors: Qianhui Qu / Weijiao Huang / Deniz Aydin / Joseph M Paggi / Alpay B Seven / Haoqing Wang / Soumen Chakraborty / Tao Che / Jeffrey F DiBerto / Michael J Robertson / Asuka Inoue / Carl-Mikael Suomivuori / Bryan L Roth / Susruta Majumdar / Ron O Dror / Brian K Kobilka / Georgios Skiniotis / Abstract: Drugs targeting the μ-opioid receptor (μOR) are the most effective analgesics available but are also associated with fatal respiratory depression through a pathway that remains unclear. Here we ...Drugs targeting the μ-opioid receptor (μOR) are the most effective analgesics available but are also associated with fatal respiratory depression through a pathway that remains unclear. Here we investigated the mechanistic basis of action of lofentanil (LFT) and mitragynine pseudoindoxyl (MP), two μOR agonists with different safety profiles. LFT, one of the most lethal opioids, and MP, a kratom plant derivative with reduced respiratory depression in animal studies, exhibited markedly different efficacy profiles for G protein subtype activation and β-arrestin recruitment. Cryo-EM structures of μOR-Gi1 complex with MP (2.5 Å) and LFT (3.2 Å) revealed that the two ligands engage distinct subpockets, and molecular dynamics simulations showed additional differences in the binding site that promote distinct active-state conformations on the intracellular side of the receptor where G proteins and β-arrestins bind. These observations highlight how drugs engaging different parts of the μOR orthosteric pocket can lead to distinct signaling outcomes. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7t2g.cif.gz | 190.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7t2g.ent.gz | 145.8 KB | Display | PDB format |
PDBx/mmJSON format | 7t2g.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/t2/7t2g ftp://data.pdbj.org/pub/pdb/validation_reports/t2/7t2g | HTTPS FTP |
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-Related structure data
Related structure data | 25612MC 7t2hC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABC
#1: Protein | Mass: 40415.031 Da / Num. of mol.: 1 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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#2: Protein | Mass: 37671.102 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 | Mass: 7861.143 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) / Strain (production host): GNG2 / References: UniProt: P59768 |
-Protein , 1 types, 1 molecules R
#4: Protein | Mass: 55123.824 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Mus musculus (house mouse) Gene: cybC, Oprm1, Mor, Oprm / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0ABE7, UniProt: P42866 |
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-Non-polymers , 3 types, 11 molecules
#5: Chemical | ChemComp-EIG / | ||
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#6: Chemical | #7: Water | ChemComp-HOH / | |
-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: mu-opioid receptor / Gi protein complex bound to mitragynine pseudoindoxyl (MP). Type: COMPLEX Details: mu-opioid receptor / Gi protein complex bound to mitragynine pseudoindoxyl (MP). Entity ID: #1-#4 / Source: MULTIPLE SOURCES |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Mus musculus (house mouse) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-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 FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 56 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software |
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EM software | Name: SerialEM / Category: image acquisition | ||||||||||||||||||||||||
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 413821 / Symmetry type: POINT | ||||||||||||||||||||||||
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