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- PDB-9o36: CryoEM structure of mu-opioid receptor - Gi protein complex bound... -

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Basic information

Entry
Database: PDB / ID: 9o36
TitleCryoEM structure of mu-opioid receptor - Gi protein complex bound to fluornitrazene (FNZ)
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Mu-type opioid receptor
  • scFv16
KeywordsMEMBRANE PROTEIN / Complex / Receptor / Agonist / MOR
Function / homology
Function and homology information


Opioid Signalling / spine apparatus / positive regulation of appetite / sperm ejaculation / G-protein activation / Peptide ligand-binding receptors / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / adenylate cyclase-inhibiting opioid receptor signaling pathway ...Opioid Signalling / spine apparatus / positive regulation of appetite / sperm ejaculation / G-protein activation / Peptide ligand-binding receptors / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / adenylate cyclase-inhibiting opioid receptor signaling pathway / negative regulation of luteinizing hormone secretion / G protein-coupled opioid receptor activity / regulation of cellular response to stress / G protein-coupled opioid receptor signaling pathway / G alpha (i) signalling events / negative regulation of nitric oxide biosynthetic process / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / presynaptic modulation of chemical synaptic transmission / dendrite membrane / dendrite cytoplasm / cellular response to forskolin / regulation of mitotic spindle organization / chemokine-mediated signaling pathway / sarcoplasmic reticulum / Regulation of insulin secretion / neuropeptide signaling pathway / locomotory behavior / excitatory postsynaptic potential / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / sarcolemma / G protein-coupled receptor binding / 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 / G alpha (12/13) signalling events / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.3 Å
AuthorsRobertson, M.J. / Skiniotis, G.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2026
Title: A µ-opioid receptor superagonist analgesic with minimal adverse effects.
Authors: Juan L Gomez / Emilya N Ventriglia / Zachary J Frangos / Agnieszka Sulima / Michael J Robertson / Michael D Sacco / Reece C Budinich / Ilinca M Giosan / Tongzhen Xie / Oscar Solis / Anna E ...Authors: Juan L Gomez / Emilya N Ventriglia / Zachary J Frangos / Agnieszka Sulima / Michael J Robertson / Michael D Sacco / Reece C Budinich / Ilinca M Giosan / Tongzhen Xie / Oscar Solis / Anna E Tischer / Jennifer M Bossert / Kiera E Caldwell / Hannah Bonbrest / Amelie Essmann / Zelai M Garçon-Poca / Shinbe Choi / Michael R Noya / Feonil Limiac / Ali Arce / Grant C Glatfelter / Margaret Robinson / Li Chen / Angelina A Mullarkey / Dain R Brademan / Garrett Enten / William Dunne / César Quiroz / Ingrid Schoenborn / Chae Bin Lee / Rana Rais / Daniel P Holt / Robert F Dannals / Lei Shi / Ruth Hüttenhain / Sergi Ferré / Eugene Kiyatkin / Jordi Bonaventura / Yavin Shaham / Venetia Zachariou / Michael H Baumann / Georgios Skiniotis / Kenner C Rice / Michael Michaelides /
Abstract: Developing safe and effective pain medications is an ongoing challenge for human health. Agonists for the µ-opioid receptor (MOR) are essential pain medications, but their high intrinsic efficacy ...Developing safe and effective pain medications is an ongoing challenge for human health. Agonists for the µ-opioid receptor (MOR) are essential pain medications, but their high intrinsic efficacy also induces adverse side effects, including respiratory depression, constipation, tolerance, dependence, withdrawal and addiction. Strategies to limit adverse effects traditionally include developing MOR agonists that have low intrinsic efficacy or that preferentially activate G-protein signalling over β-arrestin signalling. Here we identify a novel MOR agonist with supramaximal intrinsic efficacy and a unique pharmacological profile that produced effective analgesia in rodents with minimal adverse effects. N-desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called nitazenes. DFNZ has impaired brain penetrance, a unique spatiotemporal MOR cellular signalling profile, and diminished efficacy at the MOR-galanin 1 receptor (GAL1) heteromer. DFNZ does not induce respiratory depression, tolerance or MOR downregulation after repeated exposure. Compared with other MOR agonists, DFNZ has limited effects on dopamine neurotransmission in nucleus accumbens and weaker reinforcing effects in the drug self-administration procedure. These results provide novel insights about MOR and nitazene pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that high-efficacy MOR agonists cannot constitute safe and effective therapeutic agents.
History
DepositionApr 5, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 1, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 1, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 1, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 1, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 15, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.1Apr 15, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin / Data content type: EM metadata / EM metadata / EM metadata
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Revision 1.2May 13, 2026Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update
Revision 1.2May 13, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: scFv16
R: Mu-type opioid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)162,0576
Polymers161,6435
Non-polymers4141
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABC

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha 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: Trichoplusia ni (cabbage looper) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


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: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


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: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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Antibody / Protein / Non-polymers , 3 types, 3 molecules ER

#4: Antibody scFv16


Mass: 27784.896 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Trichoplusia ni (cabbage looper)
#5: Protein Mu-type opioid receptor / M-OR-1 / MOR-1


Mass: 47910.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Oprm1, Mor, Oprm / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P42866
#6: Chemical ChemComp-A1B79 / N,N-diethyl-2-(2-{[4-(2-fluoroethoxy)phenyl]methyl}-5-nitro-1H-1,3-benzimidazol-1-yl)ethan-1-amine


Mass: 414.473 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H27FN4O3 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: MOR-Gi heterotrimer complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 56 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 667110 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0028535
ELECTRON MICROSCOPYf_angle_d0.49811628
ELECTRON MICROSCOPYf_dihedral_angle_d5.2821203
ELECTRON MICROSCOPYf_chiral_restr0.041364
ELECTRON MICROSCOPYf_plane_restr0.0031452

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