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- EMDB-25613: CryoEM structure of mu-opioid receptor - Gi protein complex bound... -
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Open data
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Basic information
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Title | CryoEM structure of mu-opioid receptor - Gi protein complex bound to lofentanil (LFT) | |||||||||
![]() | CryoEM map of mu-opioid receptor / G protein complex bound to lofentanil (LFT) | |||||||||
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Function / homology | ![]() Opioid Signalling / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | |||||||||
Method | ![]() ![]() | |||||||||
![]() | Seven AB / Qu Q / Huang W / Robertson MJ / Kobilka BK / Skiniotis G | |||||||||
Funding support | ![]()
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![]() | ![]() 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 | ![]() | 59.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 20.1 KB 20.1 KB | Display Display | ![]() |
Images | ![]() | 527 KB | ||
Others | ![]() ![]() | 59.4 MB 59.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7t2hMC ![]() 7t2gC 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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Annotation | CryoEM map of mu-opioid receptor / G protein complex bound to lofentanil (LFT) | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.06 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: CryoEM half map 2 of mu-opioid receptor /...
File | emd_25613_half_map_1.map | ||||||||||||
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Annotation | CryoEM half map 2 of mu-opioid receptor / G protein complex bound to lofentanil (LFT) | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: CryoEM half map 1 of mu-opioid receptor /...
File | emd_25613_half_map_2.map | ||||||||||||
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Annotation | CryoEM half map 1 of mu-opioid receptor / G protein complex bound to lofentanil (LFT) | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : mu-opioid receptor - Gi protein complex bound to lofentanil (LFT)
Entire | Name: mu-opioid receptor - Gi protein complex bound to lofentanil (LFT) |
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Components |
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-Supramolecule #1: mu-opioid receptor - Gi protein complex bound to lofentanil (LFT)
Supramolecule | Name: mu-opioid receptor - Gi protein complex bound to lofentanil (LFT) type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 Details: mu-opioid receptor - Gi protein complex bound to lofentanil (LFT) stabilized by scFv16 |
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Source (natural) | Organism: ![]() ![]() ![]() |
-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: ![]() ![]() |
Molecular weight | Theoretical: 40.415031 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 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: ![]() ![]() |
Molecular weight | Theoretical: 37.671102 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
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: ![]() ![]() |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Macromolecule #4: scFv16
Macromolecule | Name: scFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() ![]() |
Molecular weight | Theoretical: 27.784896 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAAHHHHHH HH |
-Macromolecule #5: Mu-type opioid receptor
Macromolecule | Name: Mu-type opioid receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() ![]() |
Molecular weight | Theoretical: 39.995105 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: NISDCSDPLA PASCSPAPGS WLNLSHVDGN QSDPCGPNRT GLGENLYFQG SHSLCPQTGS PSMVTAITIM ALYSIVCVVG LFGNFLVMY VIVRYTKMKT ATNIYIFNLA LADALATSTL PFQSVNYLMG TWPFGNILCK IVISIDYYNM FTSIFTLCTM S VDRYIAVC ...String: NISDCSDPLA PASCSPAPGS WLNLSHVDGN QSDPCGPNRT GLGENLYFQG SHSLCPQTGS PSMVTAITIM ALYSIVCVVG LFGNFLVMY VIVRYTKMKT ATNIYIFNLA LADALATSTL PFQSVNYLMG TWPFGNILCK IVISIDYYNM FTSIFTLCTM S VDRYIAVC HPVKALDFRT PRNAKIVNVC NWILSSAIGL PVMFMATTKY RQGSIDCTLT FSHPTWYWEN LLKICVFIFA FI MPVLIIT VCYGLMILRL KSVRMLSGSK EKDRNLRRIT RMVLVVVAVF IVCWTPIHIY VIIKALITIP ETTFQTVSWH FCI ALGYTN SCLNPVLYAF LDENFKRCFR EFCIPTSSTI |
-Macromolecule #6: Lofentanil
Macromolecule | Name: Lofentanil / type: ligand / ID: 6 / Number of copies: 1 / Formula: EID |
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Molecular weight | Theoretical: 408.533 Da |
Chemical component information | ![]() ChemComp-EID: |
-Experimental details
-Structure determination
Method | ![]() |
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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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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
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 |
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Image processing
Initial angle assignment | Type: OTHER |
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Final angle assignment | Type: OTHER |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 152809 |