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- EMDB-70366: Structure of the MOR/Gi/Mitragynine Pseudoindoxil Complex, GTP-bo... -

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Entry
Database: EMDB / ID: EMD-70366
TitleStructure of the MOR/Gi/Mitragynine Pseudoindoxil Complex, GTP-bound G-ACT-3
Map data
Sample
  • Complex: Mu Opioid Receptor Gi1 heterotrimer complex
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Mu-type opioid receptor
  • Ligand: MAGNESIUM ION
  • Ligand: GUANOSINE-5'-TRIPHOSPHATE
  • Ligand: Mitragynine pseudoindoxyl
KeywordsGPCR / Complex / Agonist / MEMBRANE PROTEIN
Function / homology
Function and homology information


Opioid Signalling / spine apparatus / positive regulation of appetite / sperm ejaculation / G-protein activation / adenylate cyclase-inhibiting opioid receptor signaling pathway / Peptide ligand-binding receptors / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion ...Opioid Signalling / spine apparatus / positive regulation of appetite / sperm ejaculation / G-protein activation / adenylate cyclase-inhibiting opioid receptor signaling pathway / Peptide ligand-binding receptors / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / negative regulation of luteinizing hormone secretion / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / regulation of cellular response to stress / G alpha (i) signalling events / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of nitric oxide biosynthetic process / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / behavioral response to ethanol / regulation of NMDA receptor activity / neuropeptide binding / positive regulation of neurogenesis / eating behavior / negative regulation of cytosolic calcium ion concentration / transmission of nerve impulse / G-protein alpha-subunit binding / social behavior / voltage-gated calcium channel activity / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / T-tubule / sensory perception of pain / positive regulation of gluconeogenesis / dendrite membrane / cellular response to forskolin / presynaptic modulation of chemical synaptic transmission / dendrite cytoplasm / regulation of mitotic spindle organization / chemokine-mediated signaling pathway / sarcoplasmic reticulum / Regulation of insulin secretion / neuropeptide signaling pathway / response to prostaglandin E / locomotory behavior / excitatory postsynaptic potential / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / sarcolemma / response to peptide hormone / G protein-coupled receptor activity / GABA-ergic synapse / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / centriolar satellite / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / GDP binding / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G-protein beta-subunit binding / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / sensory perception of taste / adenylate cyclase-activating G protein-coupled receptor signaling pathway
Similarity search - Function
Mu opioid receptor / Opioid receptor / G-protein alpha subunit, group I / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. ...Mu opioid receptor / Opioid receptor / G-protein alpha subunit, group I / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Mu-type opioid receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsRobertson MJ / Skiniotis G
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)HD107581 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RR230042 United States
CitationJournal: Nature / Year: 2025
Title: Non-equilibrium snapshots of ligand efficacy at the μ-opioid receptor.
Authors: Michael J Robertson / Arnab Modak / Makaía M Papasergi-Scott / Miaohui Hu / Maria Claudia Peroto / Balazs R Varga / Susruta Majumdar / Ravi Kalathur / Scott C Blanchard / Georgios Skiniotis /
Abstract: Distinct ligands for the same G-protein-coupled receptor (GPCR) activate intracellular signalling partners to varying extents, but the molecular mechanisms that drive these differences remain elusive. ...Distinct ligands for the same G-protein-coupled receptor (GPCR) activate intracellular signalling partners to varying extents, but the molecular mechanisms that drive these differences remain elusive. Here, hypothesizing that such differences in signalling efficacy might be captured structurally in intermediate states under non-equilibrium conditions, we use a time-resolved cryo-electron-microscopy approach to visualize the GTP-induced activation of the Gαβγ heterotrimer by the μ-opioid receptor bound to three ligands that show partial, full or super agonism on the receptor. We resolve ensembles of conformational states along the G-protein activation pathway, including an intermediate state that enables us to visualize receptor dynamics as a function of bound ligand. The results reveal ligand-dependent differences in state occupancy and conformational stability, with higher ligand efficacy correlating with increased dynamics of the receptor's transmembrane helices 5 and 6. Furthermore, we identify key differences between G and G in the mechanism of GTP-induced activation, which are likely to underlie the distinct activation kinetics of these G-protein types. Corroborated by molecular-dynamics simulations and single-molecule fluorescence assays, our findings provide a dynamic structural landscape of GPCR-G-protein interactions for ligands of various efficacies, and suggest that partial agonists produce a 'kinetic trap' during G-protein activation.
History
DepositionApr 27, 2025-
Header (metadata) releaseJan 7, 2026-
Map releaseJan 7, 2026-
UpdateJan 7, 2026-
Current statusJan 7, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70366.png

Downloads & links

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Map

FileDownload / File: emd_70366.map.gz / Format: CCP4 / Size: 209.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.96 Å/pix.
x 380 pix.
= 364.8 Å		0.96 Å/pix.
x 380 pix.
= 364.8 Å		0.96 Å/pix.
x 380 pix.
= 364.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.96 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.43
Minimum - Maximum-1.3323487 - 2.4229531
Average (Standard dev.)-0.00035885285 (±0.03536902)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions380380380
Spacing380380380
CellA=B=C: 364.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: G protein local refinement

Fileemd_70366_additional_1.map
AnnotationG protein local refinement
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Half map: #2

Fileemd_70366_half_map_1.map
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Half map: #1

Fileemd_70366_half_map_2.map
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Sample components

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Entire : Mu Opioid Receptor Gi1 heterotrimer complex

EntireName: Mu Opioid Receptor Gi1 heterotrimer complex
Components
  • Complex: Mu Opioid Receptor Gi1 heterotrimer complex
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Mu-type opioid receptor
  • Ligand: MAGNESIUM ION
  • Ligand: GUANOSINE-5'-TRIPHOSPHATE
  • Ligand: Mitragynine pseudoindoxyl

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Supramolecule #1: Mu Opioid Receptor Gi1 heterotrimer complex

SupramoleculeName: Mu Opioid Receptor Gi1 heterotrimer complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.671102 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #3: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.415031 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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Macromolecule #4: Mu-type opioid receptor

MacromoleculeName: Mu-type opioid receptor / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 47.910758 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAMGPGNI SDCSDPLAPA SCSPAPGSWL NLSHVDGNQS DPCGPNRTGL GGSHSLCPQT GSPSMVTAI TIMALYSIVC VVGLFGNFLV MYVIVRYTKM KTATNIYIFN LALADALATS TLPFQSVNYL MGTWPFGNIL C KIVISIDY ...String:
MKTIIALSYI FCLVFADYKD DDDAMGPGNI SDCSDPLAPA SCSPAPGSWL NLSHVDGNQS DPCGPNRTGL GGSHSLCPQT GSPSMVTAI TIMALYSIVC VVGLFGNFLV MYVIVRYTKM KTATNIYIFN LALADALATS TLPFQSVNYL MGTWPFGNIL C KIVISIDY YNMFTSIFTL CTMSVDRYIA VCHPVKALDF RTPRNAKIVN VCNWILSSAI GLPVMFMATT KYRQGSIDCT LT FSHPTWY WENLLKICVF IFAFIMPVLI ITVCYGLMIL RLKSVRMLSG SKEKDRNLRR ITRMVLVVVA VFIVCWTPIH IYV IIKALI TIPETTFQTV SWHFCIALGY TNSCLNPVLY AFLDENFKRC FREFCIPTSS TIEQQNSARI RQNTREHPST ANTV DRTNH QLENLEAETA PLPDIHHHHH H

UniProtKB: Mu-type opioid receptor

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Macromolecule #5: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #6: GUANOSINE-5'-TRIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 6 / Number of copies: 1 / Formula: GTP
Molecular weightTheoretical: 523.18 Da
Chemical component information

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM

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Macromolecule #7: Mitragynine pseudoindoxyl

MacromoleculeName: Mitragynine pseudoindoxyl / type: ligand / ID: 7 / Number of copies: 1 / Formula: EIG
Molecular weightTheoretical: 414.495 Da
Chemical component information

ChemComp-EIG:
Mitragynine pseudoindoxyl

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 57982
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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