
- EMDB-28069: Morphine-bound mu-opioid receptor-Gi complex -
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Open data
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Basic information
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Title | Morphine-bound mu-opioid receptor-Gi complex | ||||||||||||
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![]() | mu-opioid receptor / G protein / morphine / 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 / positive regulation of cAMP-mediated signaling / G protein-coupled opioid receptor signaling pathway / negative regulation of nitric oxide biosynthetic process / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / behavioral response to ethanol ...Opioid Signalling / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / regulation of cellular response to stress / positive regulation of cAMP-mediated signaling / G protein-coupled opioid receptor signaling pathway / negative regulation of nitric oxide biosynthetic process / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / behavioral response to ethanol / sensory perception / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / regulation of NMDA receptor activity / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / neuropeptide binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / Thrombin signalling through proteinase activated receptors (PARs) / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / photoreceptor outer segment membrane / positive regulation of neurogenesis / G alpha (q) signalling events / negative regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / spectrin binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / negative regulation of cAMP-mediated signaling / alkylglycerophosphoethanolamine phosphodiesterase activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / photoreceptor outer segment / G-protein alpha-subunit binding / neuropeptide signaling pathway / voltage-gated calcium channel activity / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / T cell migration / D2 dopamine receptor binding / MECP2 regulates neuronal receptors and channels / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / adenylate cyclase regulator activity / sensory perception of pain / photoreceptor inner segment / cardiac muscle cell apoptotic process / cellular response to forskolin / regulation of mitotic spindle organization / Peptide ligand-binding receptors / Regulation of insulin secretion / G protein-coupled receptor binding / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / response to peptide hormone / G-protein activation / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (z) signalling events / GDP binding / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus Similarity search - Function | ||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.2 Å | ||||||||||||
![]() | Zhuang Y / Wang Y / Guo S / Zhou XE / Rao Q / He X / He B / Liu J / Zhou Q / Wang X ...Zhuang Y / Wang Y / Guo S / Zhou XE / Rao Q / He X / He B / Liu J / Zhou Q / Wang X / Liu W / Jiang X / Yang D / Chen X / Jiang Y / Jiang H / Shen J / Melcher K / Wang M / Xie X / Xu HE | ||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Molecular recognition of morphine and fentanyl by the human μ-opioid receptor. Authors: Youwen Zhuang / Yue Wang / Bingqing He / Xinheng He / X Edward Zhou / Shimeng Guo / Qidi Rao / Jiaqi Yang / Jinyu Liu / Qingtong Zhou / Xiaoxi Wang / Mingliang Liu / Weiyi Liu / Xiangrui ...Authors: Youwen Zhuang / Yue Wang / Bingqing He / Xinheng He / X Edward Zhou / Shimeng Guo / Qidi Rao / Jiaqi Yang / Jinyu Liu / Qingtong Zhou / Xiaoxi Wang / Mingliang Liu / Weiyi Liu / Xiangrui Jiang / Dehua Yang / Hualiang Jiang / Jingshan Shen / Karsten Melcher / Hong Chen / Yi Jiang / Xi Cheng / Ming-Wei Wang / Xin Xie / H Eric Xu / ![]() ![]() Abstract: Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of μ-opioid receptor (μOR). Here, ...Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of μ-opioid receptor (μOR). Here, we report structures of the human μOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of μOR bound to TRV130, PZM21, and SR17018, which reveal preferential interactions of these agonists with TM3 side of the ligand-binding pocket rather than TM6/7 side. In contrast, morphine and fentanyl form dual interactions with both TM3 and TM6/7 regions. Mutations at the TM6/7 interface abolish arrestin recruitment of μOR promoted by morphine and fentanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of μOR, which may facilitate rational design of next-generation analgesics. | ||||||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 38 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 22.1 KB 22.1 KB | Display Display | ![]() |
Images | ![]() | 117.2 KB | ||
Filedesc metadata | ![]() | 6.7 KB | ||
Others | ![]() ![]() | 31.3 MB 31.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 875.6 KB | Display | ![]() |
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Full document | ![]() | 875.2 KB | Display | |
Data in XML | ![]() | 11.1 KB | Display | |
Data in CIF | ![]() | 13.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8ef6MC ![]() 8ef5C ![]() 8efbC ![]() 8eflC ![]() 8efoC ![]() 8efqC C: citing same article ( M: atomic model generated by this map |
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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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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.071 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_28069_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_28069_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : fentanyl bound mu-opioid receptor-G protein complex
Entire | Name: fentanyl bound mu-opioid receptor-G protein complex |
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Components |
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-Supramolecule #1: fentanyl bound mu-opioid receptor-G protein complex
Supramolecule | Name: fentanyl bound mu-opioid receptor-G protein complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Mu-type opioid receptor
Macromolecule | Name: Mu-type opioid receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 41.072191 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: DSSAAPTNAS NCTDALAYSS CSPAPSPGSW VNLSHLDGNL SDPCGPNRTD LGGRDSLCPP TGSPSMITAI TIMALYSIVC VVGLFGNFL VMYVIVRYTK MKTATNIYIF NLALADALAT STLPFQSVNY LMGTWPFGTI LCKIVISIDY YNMFTSIFTL C TMSVDRYI ...String: DSSAAPTNAS NCTDALAYSS CSPAPSPGSW VNLSHLDGNL SDPCGPNRTD LGGRDSLCPP TGSPSMITAI TIMALYSIVC VVGLFGNFL VMYVIVRYTK MKTATNIYIF NLALADALAT STLPFQSVNY LMGTWPFGTI LCKIVISIDY YNMFTSIFTL C TMSVDRYI AVCHPVKALD FRTPRNAKII NVCNWILSSA IGLPVMFMAT TKYRQGSIDC TLTFSHPTWY WENLLKICVF IF AFIMPVL IITVCYGLMI LRLKSVRMLS GSKEKDRNLR RITRMVLVVV AVFIVCWTPI HIYVIIKALV TIPETTFQTV SWH FCIALG YTNSCLNPVL YAFLDENFKR CFREFCIPTS SNIEQQNSTR I UniProtKB: Mu-type opioid receptor |
-Macromolecule #2: 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: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 40.445059 KDa |
Recombinant expression | Organism: ![]() ![]() |
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 FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 39.020664 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MHHHHHHHHG SLLQSELDQL RQEAEQLKNQ IRDARKACAD ATLSQITNNI DPVGRIQMRT RRTLRGHLAK IYAMHWGTDS RLLVSASQD GKLIIWDSYT TNKVHAIPLR SSWVMTCAYA PSGNYVACGG LDNICSIYNL KTREGNVRVS RELAGHTGYL S CCRFLDDN ...String: MHHHHHHHHG SLLQSELDQL RQEAEQLKNQ IRDARKACAD ATLSQITNNI DPVGRIQMRT RRTLRGHLAK IYAMHWGTDS RLLVSASQD GKLIIWDSYT TNKVHAIPLR SSWVMTCAYA PSGNYVACGG LDNICSIYNL KTREGNVRVS RELAGHTGYL S CCRFLDDN QIVTSSGDTT CALWDIETGQ QTTTFTGHTG DVMSLSLAPD TRLFVSGACD ASAKLWDVRE GMCRQTFTGH ES DINAICF FPNGNAFATG SDDATCRLFD LRADQELMTY SHDNIICGIT SVSFSKSGRL LLAGYDDFNC NVWDALKADR AGV LAGHDN RVSCLGVTDD GMAVATGSWD SFLKIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #4: 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: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 7.56375 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFC UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #5: scFV16
Macromolecule | Name: scFV16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 26.408492 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SAGGGGSGGG GSGGGGSADI VMTQATSSVP VTPGESVSIS C RSSKSLLH ...String: MVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SAGGGGSGGG GSGGGGSADI VMTQATSSVP VTPGESVSIS C RSSKSLLH SNGNTYLYWF LQRPGQSPQL LIYRMSNLAS GVPDRFSGSG SGTAFTLTIS RLEAEDVGVY YCMQHLEYPL TF GAGTKLE L |
-Macromolecule #6: (7R,7AS,12BS)-3-METHYL-2,3,4,4A,7,7A-HEXAHYDRO-1H-4,12-METHANO[1]...
Macromolecule | Name: (7R,7AS,12BS)-3-METHYL-2,3,4,4A,7,7A-HEXAHYDRO-1H-4,12-METHANO[1]BENZOFURO[3,2-E]ISOQUINOLINE-7,9-DIOL type: ligand / ID: 6 / Number of copies: 2 / Formula: MOI |
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Molecular weight | Theoretical: 285.338 Da |
Chemical component information | ![]() ChemComp-MOI: |
-Macromolecule #7: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 10 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ![]() ChemComp-CLR: |
-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: 7.2 |
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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 K3 (6k x 4k) / Average electron dose: 70.0 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: 3.0 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: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 382346 |
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |