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Yorodumi- EMDB-25612: CryoEM structure of mu-opioid receptor - Gi protein complex bound... -
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-Basic information
Entry | Database: EMDB / ID: EMD-25612 | |||||||||
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Title | CryoEM structure of mu-opioid receptor - Gi protein complex bound to mitragynine pseudoindoxyl (MP) | |||||||||
Map data | CryoEM map of mu-opioid receptor / G protein complex bound to mitragynine pseudoindoxyl (MP). | |||||||||
Sample |
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Function / homology | Function and homology information Opioid Signalling / spine apparatus / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / adenylate cyclase-inhibiting opioid receptor signaling pathway / positive regulation of appetite / G-protein activation ...Opioid Signalling / spine apparatus / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / behavioral response to ethanol / negative regulation of nitric oxide biosynthetic process / neuropeptide binding / negative regulation of cAMP-mediated signaling / positive regulation of neurogenesis / eating behavior / negative regulation of cytosolic calcium ion concentration / transmission of nerve impulse / regulation of NMDA receptor activity / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / neuropeptide signaling pathway / G-protein alpha-subunit binding / GABA-ergic synapse / voltage-gated calcium channel activity / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / positive regulation of cAMP-mediated signaling / regulation of mitotic spindle organization / cellular response to forskolin / sensory perception of pain / dendrite membrane / excitatory postsynaptic potential / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / presynaptic modulation of chemical synaptic transmission / dendrite cytoplasm / locomotory behavior / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / Olfactory Signaling Pathway / G-protein beta/gamma-subunit complex binding / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating 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 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / GDP binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / 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 / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation Similarity search - Function | |||||||||
Biological species | Mus musculus (house mouse) / Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.5 Å | |||||||||
Authors | Seven AB / Qu Q / Robertson MJ / Wang H / Kobilka BK / Skiniotis G | |||||||||
Funding support | United States, 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_25612.map.gz | 1.6 MB | EMDB map data format | |
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Header (meta data) | emd-25612-v30.xml emd-25612.xml | 19.6 KB 19.6 KB | Display Display | EMDB header |
Images | emd_25612.png | 525 KB | ||
Others | emd_25612_additional_1.map.gz emd_25612_additional_2.map.gz | 3.4 MB 5.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-25612 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-25612 | HTTPS FTP |
-Related structure data
Related structure data | 7t2gMC 7t2hC 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_25612.map.gz / Format: CCP4 / Size: 28.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | CryoEM map of mu-opioid receptor / G protein complex bound to mitragynine pseudoindoxyl (MP). | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.82 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: Locally refined map of mu-opioid receptor.
File | emd_25612_additional_1.map | ||||||||||||
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Annotation | Locally refined map of mu-opioid receptor. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Locally refined map of G protein heterotrimer.
File | emd_25612_additional_2.map | ||||||||||||
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Annotation | Locally refined map of G protein heterotrimer. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : mu-opioid receptor / Gi protein complex bound to mitragynine pseu...
Entire | Name: mu-opioid receptor / Gi protein complex bound to mitragynine pseudoindoxyl (MP). |
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Components |
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-Supramolecule #1: mu-opioid receptor / Gi protein complex bound to mitragynine pseu...
Supramolecule | Name: mu-opioid receptor / Gi protein complex bound to mitragynine pseudoindoxyl (MP). type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#4 Details: mu-opioid receptor / Gi protein complex bound to mitragynine pseudoindoxyl (MP). |
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Source (natural) | Organism: Mus musculus (house mouse) |
-Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 40.415031 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKDCGLF |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 37.671102 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT ...String: PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DASAKLWDVR EGMCRQTFTG HESDINAICF FP NGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLLAGYDDFN CNVWDALKAD RAGVLAGHDN RVS CLGVTD DGMAVATGSW DSFLKIWN |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Macromolecule #4: Soluble cytochrome b562,Mu-type opioid receptor
Macromolecule | Name: Soluble cytochrome b562,Mu-type opioid receptor / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 55.123824 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: CLVFADYKDD DDALEVLFQG PADLEDNWET LNDNLKVIEK ADNAAQVKDA LTKMRAAALD AQKATPPKLE DKSPDSPEMK DFRHGFDIL VGQIDDALKL ANEGKVKEAQ AAAEQLKTTR NAYIQKYLAG SPGARSASSL ALAIAITALY SIVCVVGLFG N FLVMYVIV ...String: CLVFADYKDD DDALEVLFQG PADLEDNWET LNDNLKVIEK ADNAAQVKDA LTKMRAAALD AQKATPPKLE DKSPDSPEMK DFRHGFDIL VGQIDDALKL ANEGKVKEAQ AAAEQLKTTR NAYIQKYLAG SPGARSASSL ALAIAITALY SIVCVVGLFG N FLVMYVIV RYTKMKTATN IYIFNLALAD ALATSTLPFQ SVNYLMGTWP FGNILCKIVI SIDYYNMFTS IFTLCTMSVD RY IAVCHPV KALDFRTPRN AKIVNVCNWI LSSAIGLPVM FMATTKYRQG SIDCTLTFSH PTWYWENLLK ICVFIFAFIM PVL IITVCY GLMILRLKSV RMLSGSKEKD RNLRRITRMV LVVVAVFIVC WTPIHIYVII KALITIPETT FQTVSWHFCI ALGY TNSCL NPVLYAFLDE NFKRCFREFC IPTSSTILEV LFQGPEQQNS ARIRQNTREH PSTANTVDRT NHQLENLEAE TAPLP DIHH HHHH |
-Macromolecule #5: Mitragynine pseudoindoxyl
Macromolecule | Name: Mitragynine pseudoindoxyl / type: ligand / ID: 5 / Number of copies: 1 / Formula: EIG |
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Molecular weight | Theoretical: 414.495 Da |
Chemical component information | ChemComp-EIG: |
-Macromolecule #6: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 2 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-Macromolecule #7: water
Macromolecule | Name: water / type: ligand / ID: 7 / Number of copies: 8 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 56.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Initial angle assignment | Type: OTHER |
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Final angle assignment | Type: OTHER |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 413821 |