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- PDB-8dzs: GR89,696 bound Kappa Opioid Receptor in complex with Gz -

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Basic information

Entry
Database: PDB / ID: 8dzs
TitleGR89,696 bound Kappa Opioid Receptor in complex with Gz
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Kappa-type opioid receptor
  • ScFv16 protein
KeywordsMEMBRANE PROTEIN / GPCR / Kappa opioid receptor / G protein
Function / homology
Function and homology information


adenylate cyclase inhibitor activity / dynorphin receptor activity / response to acrylamide / regulation of saliva secretion / negative regulation of luteinizing hormone secretion / G protein-coupled serotonin receptor signaling pathway / positive regulation of eating behavior / sensory perception of temperature stimulus / adenylate cyclase-inhibiting opioid receptor signaling pathway / G protein-coupled opioid receptor activity ...adenylate cyclase inhibitor activity / dynorphin receptor activity / response to acrylamide / regulation of saliva secretion / negative regulation of luteinizing hormone secretion / G protein-coupled serotonin receptor signaling pathway / positive regulation of eating behavior / sensory perception of temperature stimulus / adenylate cyclase-inhibiting opioid receptor signaling pathway / G protein-coupled opioid receptor activity / conditioned place preference / G protein-coupled opioid receptor signaling pathway / positive regulation of dopamine secretion / positive regulation of potassium ion transmembrane transport / sensory perception / maternal behavior / neuropeptide binding / receptor serine/threonine kinase binding / positive regulation of p38MAPK cascade / eating behavior / behavioral response to cocaine / estrous cycle / neuropeptide signaling pathway / negative regulation of insulin secretion / G protein-coupled serotonin receptor binding / axon terminus / MECP2 regulates neuronal receptors and channels / sensory perception of pain / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / locomotory behavior / G protein-coupled receptor binding / cellular response to glucose stimulus / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / response to insulin / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / synaptic vesicle membrane / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / response to estrogen / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / presynaptic membrane / nuclear envelope / cell body / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / perikaryon / chemical synaptic transmission / G alpha (s) signalling events / postsynaptic membrane / G alpha (q) signalling events / defense response to virus / response to ethanol / Ras protein signal transduction / cellular response to lipopolysaccharide / cell population proliferation / Extra-nuclear estrogen signaling / neuron projection / immune response / G protein-coupled receptor signaling pathway / lysosomal membrane
Similarity search - Function
Kappa opioid receptor / Opioid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit ...Kappa opioid receptor / Opioid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-U9I / Guanine nucleotide-binding protein G(z) subunit alpha / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.65 Å
AuthorsFay, J.F. / Che, T.
Funding support United States, 1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2023Provider: repository / Type: Initial release
Revision 1.1May 17, 2023Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 24, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Kappa-type opioid receptor
B: Guanine nucleotide-binding protein G(z) subunit alpha
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: ScFv16 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)147,0196
Polymers146,6055
Non-polymers4141
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#2: Protein Guanine nucleotide-binding protein G(z) subunit alpha / G(x) alpha chain / Gz-alpha


Mass: 39849.551 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAZ / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P19086
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37285.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#4: 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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

#1: Protein Kappa-type opioid receptor / K-OR-1 / KOR-1


Mass: 34928.555 Da / Num. of mol.: 1 / Mutation: I135L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: OPRK1, OPRK / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41145
#5: Antibody ScFv16 protein


Mass: 26679.721 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Chemical ChemComp-U9I / methyl (3R)-4-[(3,4-dichlorophenyl)acetyl]-3-[(pyrrolidin-1-yl)methyl]piperazine-1-carboxylate


Mass: 414.326 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H25Cl2N3O3 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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: GR89,696 bound Kappa Opioid Receptor in complex with Gz
Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
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-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 100 nm
Image recordingElectron dose: 29.07 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 5752

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM softwareName: cryoSPARC / Version: 3.2 / Category: image acquisition
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 643193 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048406
ELECTRON MICROSCOPYf_angle_d0.75311429
ELECTRON MICROSCOPYf_dihedral_angle_d5.6971191
ELECTRON MICROSCOPYf_chiral_restr0.051357
ELECTRON MICROSCOPYf_plane_restr0.0051427

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