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- EMDB-27806: GR89,696 bound Kappa Opioid Receptor in complex with gustducin -

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Entry
Database: EMDB / ID: EMD-27806
TitleGR89,696 bound Kappa Opioid Receptor in complex with gustducin
Map datadeep sharp
Sample
  • Complex: GR89,696 bound Kappa Opioid Receptor in complex with gustducin
    • Protein or peptide: Kappa-type opioid receptor
    • Protein or peptide: G alpha gustducin protein
    • 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: ScFv16 protein
  • Ligand: methyl (3R)-4-[(3,4-dichlorophenyl)acetyl]-3-[(pyrrolidin-1-yl)methyl]piperazine-1-carboxylate
KeywordsGPCR / Kappa opioid receptor / G protein / MEMBRANE PROTEIN
Function / homology
Function and homology information


response to acrylamide / dynorphin receptor activity / regulation of saliva secretion / sensory perception of temperature stimulus / positive regulation of eating behavior / adenylate cyclase-inhibiting opioid receptor signaling pathway / negative regulation of luteinizing hormone secretion / G protein-coupled opioid receptor activity / maternal behavior / G protein-coupled opioid receptor signaling pathway ...response to acrylamide / dynorphin receptor activity / regulation of saliva secretion / sensory perception of temperature stimulus / positive regulation of eating behavior / adenylate cyclase-inhibiting opioid receptor signaling pathway / negative regulation of luteinizing hormone secretion / G protein-coupled opioid receptor activity / maternal behavior / G protein-coupled opioid receptor signaling pathway / positive regulation of dopamine secretion / positive regulation of potassium ion transmembrane transport / receptor serine/threonine kinase binding / positive regulation of p38MAPK cascade / neuropeptide binding / sensory perception / eating behavior / estrous cycle / conditioned place preference / MECP2 regulates neuronal receptors and channels / behavioral response to cocaine / sensory perception of pain / T-tubule / locomotory behavior / axon terminus / Peptide ligand-binding receptors / sarcoplasmic reticulum / response to nicotine / cellular response to glucose stimulus / neuropeptide signaling pathway / response to insulin / response to estrogen / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / phospholipase C-activating G protein-coupled receptor 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 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / synaptic vesicle membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to lipopolysaccharide / GPER1 signaling / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / G-protein beta-subunit binding / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / GTPase binding / presynaptic membrane / chemical synaptic transmission / Ca2+ pathway / defense response to virus / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / response to ethanol / G alpha (q) signalling events / perikaryon / Ras protein signal transduction / postsynaptic membrane / Extra-nuclear estrogen signaling / neuron projection / immune response / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / dendrite / protein-containing complex binding / signal transduction / mitochondrion / extracellular exosome / membrane / plasma membrane
Similarity search - Function
Kappa opioid receptor / Opioid receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 ...Kappa opioid receptor / Opioid receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 / Guanine nucleotide-binding protein, beta subunit / G protein beta WD-40 repeat protein / 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
Similarity search - Domain/homology
Kappa-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
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsFay JF / Che T
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM143061 United States
CitationJournal: Nature / Year: 2023
Title: Ligand and G-protein selectivity in the κ-opioid receptor.
Authors: Jianming Han / Jingying Zhang / Antonina L Nazarova / Sarah M Bernhard / Brian E Krumm / Lei Zhao / Jordy Homing Lam / Vipin A Rangari / Susruta Majumdar / David E Nichols / Vsevolod ...Authors: Jianming Han / Jingying Zhang / Antonina L Nazarova / Sarah M Bernhard / Brian E Krumm / Lei Zhao / Jordy Homing Lam / Vipin A Rangari / Susruta Majumdar / David E Nichols / Vsevolod Katritch / Peng Yuan / Jonathan F Fay / Tao Che /
Abstract: The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders. However, the development of KOR analgesics has ...The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects. The initiation of KOR signalling requires the G-family proteins including the conventional (G, G, G, G and G) and nonconventional (G and G) subtypes. How hallucinogens exert their actions through KOR and how KOR determines G-protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in a complex with multiple G-protein heterotrimers-G, G, G and G-using cryo-electron microscopy. The KOR-G-protein complexes are bound to hallucinogenic salvinorins or highly selective KOR agonists. Comparisons of these structures reveal molecular determinants critical for KOR-G-protein interactions as well as key elements governing G-family subtype selectivity and KOR ligand selectivity. Furthermore, the four G-protein subtypes display an intrinsically different binding affinity and allosteric activity on agonist binding at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR.
History
DepositionAug 8, 2022-
Header (metadata) releaseMay 3, 2023-
Map releaseMay 3, 2023-
UpdateMay 14, 2025-
Current statusMay 14, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27806.png

Downloads & links

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Map

FileDownload / File: emd_27806.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationdeep sharp
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
0.88 Å/pix.
x 288 pix.
= 253.44 Å		0.88 Å/pix.
x 288 pix.
= 253.44 Å		0.88 Å/pix.
x 288 pix.
= 253.44 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.88 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0695
Minimum - Maximum-0.0206857 - 1.8582568
Average (Standard dev.)0.0009897104 (±0.020072076)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 253.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: bfact sharp

Fileemd_27806_additional_1.map
Annotationbfact sharp
Projections & Slices
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Half map: half B

Fileemd_27806_half_map_1.map
Annotationhalf B
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Histogram (log scale)

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Half map: half A

Fileemd_27806_half_map_2.map
Annotationhalf A
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Sample components

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Entire : GR89,696 bound Kappa Opioid Receptor in complex with gustducin

EntireName: GR89,696 bound Kappa Opioid Receptor in complex with gustducin
Components
  • Complex: GR89,696 bound Kappa Opioid Receptor in complex with gustducin
    • Protein or peptide: Kappa-type opioid receptor
    • Protein or peptide: G alpha gustducin protein
    • 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: ScFv16 protein
  • Ligand: methyl (3R)-4-[(3,4-dichlorophenyl)acetyl]-3-[(pyrrolidin-1-yl)methyl]piperazine-1-carboxylate

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Supramolecule #1: GR89,696 bound Kappa Opioid Receptor in complex with gustducin

SupramoleculeName: GR89,696 bound Kappa Opioid Receptor in complex with gustducin
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Kappa-type opioid receptor

MacromoleculeName: Kappa-type opioid receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 32.289387 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GSISPAIPVI ITAVYSVVFV VGLVGNSLVM FVIIRYTKMK TATNIYIFNL ALADALVTTT MPFQSTVYLM NSWPFGDVLC KIVLSIDYY NMFTSIFTLT MMSVDRYIAV CHPVKALDFR TPLKAKIINI CIWLLSSSVG ISAIVLGGTK VREDVDVIEC S LQFPDDDY ...String:
GSISPAIPVI ITAVYSVVFV VGLVGNSLVM FVIIRYTKMK TATNIYIFNL ALADALVTTT MPFQSTVYLM NSWPFGDVLC KIVLSIDYY NMFTSIFTLT MMSVDRYIAV CHPVKALDFR TPLKAKIINI CIWLLSSSVG ISAIVLGGTK VREDVDVIEC S LQFPDDDY SWWDLFMKIC VFIFAFVIPV LIIIVCYTLM ILRLKSVRLL SGSREKDRNL RRITRLVLVV VAVFVVCWTP IH IFILVEA LGSTSHSTAA LSSYYFCIAL GYTNSSLNPI LYAFLDENFK

UniProtKB: Kappa-type opioid receptor

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Macromolecule #2: G alpha gustducin protein

MacromoleculeName: G alpha gustducin protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.340898 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSTVSAEDK AAAERSKMID KNLREDAERD ARTVKLLLLG AGESGKATIV KQMKIIHKNG YSEQECMEFK AVIYSNTLQS ILAIVKAMT TLGIDYVNPR SAEDQRQLYA MANTLEDGGM TPQLAEVIKR LWRDPGIQAC FERASEYQLN DSAAYYLNDL D RITASGYV ...String:
MGSTVSAEDK AAAERSKMID KNLREDAERD ARTVKLLLLG AGESGKATIV KQMKIIHKNG YSEQECMEFK AVIYSNTLQS ILAIVKAMT TLGIDYVNPR SAEDQRQLYA MANTLEDGGM TPQLAEVIKR LWRDPGIQAC FERASEYQLN DSAAYYLNDL D RITASGYV PNEQDVLHSR VKTTGIIETQ FSFKDLHFRM FDVGAQRSER KKWIHCFEGV TCIIFCAALS AYDMVLVEDE EV NRMHASL KLFDSICNHK YFSDTSIVLF LNKKDIFQEK VTKVHLSICF PEYTGPNTFE DAGNYIKNQF LDLNLKKEDK EIY SHMTCS TDTQNVKFVF DAVTDIIIKE NLKDCGLF

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.285734 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW ...String:
SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NAICFFPNGN AF ATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGHDNRVSCL GVT DDGMAV ATGSWDSFLK IWN

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

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Macromolecule #4: 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: 4 / 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 #5: ScFv16 protein

MacromoleculeName: ScFv16 protein / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.679721 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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 KAAA

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Macromolecule #6: methyl (3R)-4-[(3,4-dichlorophenyl)acetyl]-3-[(pyrrolidin-1-yl)me...

MacromoleculeName: methyl (3R)-4-[(3,4-dichlorophenyl)acetyl]-3-[(pyrrolidin-1-yl)methyl]piperazine-1-carboxylate
type: ligand / ID: 6 / Number of copies: 1 / Formula: U9I
Molecular weightTheoretical: 414.326 Da
Chemical component information

ChemComp-U9I:
methyl (3R)-4-[(3,4-dichlorophenyl)acetyl]-3-[(pyrrolidin-1-yl)methyl]piperazine-1-carboxylate

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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-PROPANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 5752 / Average electron dose: 29.07 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.4 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 725271
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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