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- EMDB-43648: Kappa opioid receptor:Galphai protein in complex with inverse ago... -

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Basic information

Entry
Database: EMDB / ID: EMD-43648
TitleKappa opioid receptor:Galphai protein in complex with inverse agonist JDTic, Original map receptor
Map dataOriginal map, KOR:Gi:scFv16:JDTic receptor
Sample
  • Complex: Kappa opioid receptor in complex with heterotrimeric G protein (Gai/b/g) and inverse agonist JDTic
    • Protein or peptide: Kappa opioid receptor
KeywordsG protein coupled receptor / Opioid receptor / MEMBRANE PROTEIN
Function / homology
Function and homology information


response to acrylamide / adenylate cyclase-inhibiting opioid receptor signaling pathway / dynorphin receptor activity / regulation of saliva secretion / negative regulation of luteinizing hormone secretion / sensory perception of temperature stimulus / positive regulation of eating behavior / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / positive regulation of dopamine secretion ...response to acrylamide / adenylate cyclase-inhibiting opioid receptor signaling pathway / dynorphin receptor activity / regulation of saliva secretion / negative regulation of luteinizing hormone secretion / sensory perception of temperature stimulus / positive regulation of eating behavior / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / positive regulation of dopamine secretion / sensory perception / maternal behavior / positive regulation of potassium ion transmembrane transport / receptor serine/threonine kinase binding / neuropeptide binding / positive regulation of p38MAPK cascade / eating behavior / conditioned place preference / neuropeptide signaling pathway / estrous cycle / MECP2 regulates neuronal receptors and channels / behavioral response to cocaine / axon terminus / sensory perception of pain / T-tubule / Peptide ligand-binding receptors / sarcoplasmic reticulum / response to nicotine / locomotory behavior / cellular response to glucose stimulus / response to insulin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to estrogen / synaptic vesicle membrane / cellular response to lipopolysaccharide / presynaptic membrane / response to ethanol / perikaryon / G alpha (i) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / defense response to virus / chemical synaptic transmission / postsynaptic membrane / neuron projection / immune response / dendrite / mitochondrion / nucleoplasm / membrane / plasma membrane / cytosol
Similarity search - Function
Kappa opioid receptor / Opioid receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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
Kappa-type opioid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsGati C / Motiwala Z / Tyson AS / Styrpejko D / Han GW / Khan S / Ramos-Gonzalez N / Shenvi R / Majumdar S
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM144965 United States
National Institutes of Health/National Center for Complementary and Integrative Health (NIH/NCCIH)AT012075 United States
CitationJournal: Nat Chem Biol / Year: 2025
Title: Molecular mechanisms of inverse agonism via κ-opioid receptor-G protein complexes.
Authors: Aaliyah S Tyson / Saif Khan / Zenia Motiwala / Gye Won Han / Zixin Zhang / Mohsen Ranjbar / Daniel Styrpejko / Nokomis Ramos-Gonzalez / Stone Woo / Kelly Villers / Delainey Landaker / Terry ...Authors: Aaliyah S Tyson / Saif Khan / Zenia Motiwala / Gye Won Han / Zixin Zhang / Mohsen Ranjbar / Daniel Styrpejko / Nokomis Ramos-Gonzalez / Stone Woo / Kelly Villers / Delainey Landaker / Terry Kenakin / Ryan Shenvi / Susruta Majumdar / Cornelius Gati /
Abstract: Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex ...Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist. The pharmacological impact of agonist-free receptor-G protein complexes is poorly understood. Here we present biochemical evidence that certain κ-opioid receptor (KOR) inverse agonists can act via KOR-G protein complexes. To investigate this phenomenon, we determined cryo-EM structures of KOR-G protein complexes with three inverse agonists: JDTic, norBNI and GB18, corresponding to structures of inverse agonist-bound GPCR-G protein complexes. Remarkably, the orthosteric binding pocket resembles the G protein-free 'inactive' receptor conformation, while the receptor remains coupled to the G protein. In summary, our work challenges the canonical model of receptor antagonism and offers crucial insights into GPCR pharmacology.
History
DepositionFeb 7, 2024-
Header (metadata) releaseFeb 5, 2025-
Map releaseFeb 5, 2025-
UpdateFeb 5, 2025-
Current statusFeb 5, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43648.png

Downloads & links

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Map

FileDownload / File: emd_43648.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationOriginal map, KOR:Gi:scFv16:JDTic receptor
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.29 Å/pix.
x 256 pix.
= 331.264 Å		1.29 Å/pix.
x 256 pix.
= 331.264 Å		1.29 Å/pix.
x 256 pix.
= 331.264 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.294 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-0.7753646 - 1.8761128
Average (Standard dev.)-0.0008584325 (±0.03322531)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 331.264 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Sharpened map, KOR:Gi:scFv16:JDTic receptor

Fileemd_43648_additional_1.map
AnnotationSharpened map, KOR:Gi:scFv16:JDTic receptor
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Original half map A, KOR:Gi:scFv16:JDTic receptor

Fileemd_43648_half_map_1.map
AnnotationOriginal half map A, KOR:Gi:scFv16:JDTic receptor
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Original half map B, KOR:Gi:scFv16:JDTic receptor

Fileemd_43648_half_map_2.map
AnnotationOriginal half map B, KOR:Gi:scFv16:JDTic receptor
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Kappa opioid receptor in complex with heterotrimeric G protein (G...

EntireName: Kappa opioid receptor in complex with heterotrimeric G protein (Gai/b/g) and inverse agonist JDTic
Components
  • Complex: Kappa opioid receptor in complex with heterotrimeric G protein (Gai/b/g) and inverse agonist JDTic
    • Protein or peptide: Kappa opioid receptor

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Supramolecule #1: Kappa opioid receptor in complex with heterotrimeric G protein (G...

SupramoleculeName: Kappa opioid receptor in complex with heterotrimeric G protein (Gai/b/g) and inverse agonist JDTic
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 130 kDa/nm

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Macromolecule #1: Kappa opioid receptor

MacromoleculeName: Kappa opioid receptor / type: protein_or_peptide / ID: 1 / Enantiomer: DEXTRO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera (butterflies/moths)
SequenceString: MDSPIQIFRG EPGPTCAPSA CLPPNSSAWF PGWAEPDSNG SAGSEDAQLE PAHISPAIPV IITAVYSVV FVVGLVGNSL VMFVIIRYTK MKTATNIYIF NLALADALVT TTMPFQSTVY L MNSWPFGD VLCKIVISID YYNMFTSIFT LTMMSVDRYI AVCHPVKALD ...String:
MDSPIQIFRG EPGPTCAPSA CLPPNSSAWF PGWAEPDSNG SAGSEDAQLE PAHISPAIPV IITAVYSVV FVVGLVGNSL VMFVIIRYTK MKTATNIYIF NLALADALVT TTMPFQSTVY L MNSWPFGD VLCKIVISID YYNMFTSIFT LTMMSVDRYI AVCHPVKALD FRTPLKAKII NI CIWLLSS SVGISAIVLG GTKVREDVDV IECSLQFPDD DYSWWDLFMK ICVFIFAFVI PVL IIIVCY TLMILRLKSV RLLSGSREKD RNLRRITRLV LVVVAVFVVC WTPIHIFILV EALG STSHS TAALSSYYFC IALGYTNSSL NPILYAFLDE NFKRCFRDFC FPLKMRMERQ STSRV RNTV QDPAYLRDID GMNKPV

UniProtKB: Kappa-type opioid receptor

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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

Concentration18 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
20.0 mMHEPESHEPES
150.0 mMNaClsodium chloride
0.001 %LMNGdetergent
GridModel: Quantifoil / Material: GOLD / Mesh: 200 / Support film - Material: GOLD / Support film - topology: HOLEY ARRAY
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated magnification: 105000 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: -25.0 µm / Nominal defocus min: -15.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL / In silico model: Ab initio
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v4.5.3) / Number images used: 330302
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. v4.5.3)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. v4.5.3)
Final 3D classificationNumber classes: 2 / Software - Name: cryoSPARC (ver. v4.5.3)

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