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- PDB-9bjk: Inactive mu opioid receptor bound to Nb6, naloxone and NAM -

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Basic information

Entry
Database: PDB / ID: 9bjk
TitleInactive mu opioid receptor bound to Nb6, naloxone and NAM
Components
  • Mu-type opioid receptor
  • kappa opioid receptor Nanobody 6
KeywordsMEMBRANE PROTEIN / G-protein coupled receptor / inactive / opioid / allosteric modulator
Function / homology
Function and homology information


Opioid Signalling / Peptide ligand-binding receptors / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / G-protein activation / G protein-coupled opioid receptor activity / negative regulation of cAMP-mediated signaling / G protein-coupled opioid receptor signaling pathway / G alpha (i) signalling events ...Opioid Signalling / Peptide ligand-binding receptors / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / G-protein activation / G protein-coupled opioid receptor activity / negative regulation of cAMP-mediated signaling / G protein-coupled opioid receptor signaling pathway / G alpha (i) signalling events / negative regulation of nitric oxide biosynthetic process / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / regulation of NMDA receptor activity / positive regulation of neurogenesis / negative regulation of cytosolic calcium ion concentration / transmission of nerve impulse / G-protein alpha-subunit binding / sensory perception of pain / presynaptic modulation of chemical synaptic transmission / GABA-ergic synapse / locomotory behavior / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G protein-coupled receptor activity / adenylate cyclase-activating dopamine receptor signaling pathway / presynapse / phospholipase C-activating G protein-coupled receptor signaling pathway / perikaryon / positive regulation of ERK1 and ERK2 cascade / endosome / axon / dendrite / membrane / plasma membrane
Similarity search - Function
Mu opioid receptor / Opioid receptor / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
: / : / Mu-type opioid receptor
Similarity search - Component
Biological speciesLama glama (llama)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.26 Å
AuthorsO'Brien, E.S. / Wang, H. / Kaavya Krishna, K. / Zhang, C. / Kobilka, B.K.
Funding support United States, 1items
OrganizationGrant numberCountry
Chan Zuckerberg Initiative United States
CitationJournal: Nature / Year: 2024
Title: A µ-opioid receptor modulator that works cooperatively with naloxone.
Authors: Evan S O'Brien / Vipin Ashok Rangari / Amal El Daibani / Shainnel O Eans / Haylee R Hammond / Elizabeth White / Haoqing Wang / Yuki Shiimura / Kaavya Krishna Kumar / Qianru Jiang / Kevin ...Authors: Evan S O'Brien / Vipin Ashok Rangari / Amal El Daibani / Shainnel O Eans / Haylee R Hammond / Elizabeth White / Haoqing Wang / Yuki Shiimura / Kaavya Krishna Kumar / Qianru Jiang / Kevin Appourchaux / Weijiao Huang / Chensong Zhang / Brandon J Kennedy / Jesper M Mathiesen / Tao Che / Jay P McLaughlin / Susruta Majumdar / Brian K Kobilka /
Abstract: The µ-opioid receptor (µOR) is a well-established target for analgesia, yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These ...The µ-opioid receptor (µOR) is a well-established target for analgesia, yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl, a highly potent synthetic opioid. µOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive. Here we screened a large DNA-encoded chemical library against inactive µOR, counter-screening with active, G-protein and agonist-bound receptor to 'steer' hits towards conformationally selective modulators. We discovered a NAM compound with high and selective enrichment to inactive µOR that enhances the affinity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling. Using cryogenic electron microscopy, we demonstrate that the NAM accomplishes this effect by binding a site on the extracellular vestibule in direct contact with naloxone while stabilizing a distinct inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone to effectively inhibit various morphine-induced and fentanyl-induced behavioural effects in vivo while minimizing withdrawal behaviours. Our results provide detailed structural insights into the mechanism of negative allosteric modulation of the µOR and demonstrate how this can be exploited in vivo.
History
DepositionApr 25, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 17, 2024Provider: repository / Type: Initial release
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Revision 1.1Jul 24, 2024Group: 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 1.2Aug 14, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 1.3Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.4May 21, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 21, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
N: kappa opioid receptor Nanobody 6
R: Mu-type opioid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,5844
Polymers62,6512
Non-polymers9332
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein kappa opioid receptor Nanobody 6


Mass: 14730.255 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#2: Protein Mu-type opioid receptor / M-OR-1 / MOR-1


Mass: 47920.734 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
#3: Chemical ChemComp-A1APV / Naloxone / 3,14-dihydroxy-17-(prop-2-en-1-yl)-5alpha-4,5-epoxymorphinan-6-one


Mass: 327.374 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H21NO4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-A1APU / Nalpha-[({(1M)-1-[5-(benzyloxy)pyridin-3-yl]naphthalen-2-yl}sulfanyl)acetyl]-3-methoxy-N,4-dimethyl-L-phenylalaninamide


Mass: 605.746 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H35N3O4S / Feature type: SUBJECT OF INVESTIGATION
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: mu-type opioid receptor with kappa-type opioid receptor ICL3 in complex with Nb6, naloxone and a negative allosteric modulator
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1400 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 128613 / Symmetry type: POINT

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