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- PDB-8y45: Cryo-EM structure of opioid receptor with biased agonist -

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Basic information

Entry
Database: PDB / ID: 8y45
TitleCryo-EM structure of opioid receptor with biased agonist
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Delta-type opioid receptor
  • scFv16
KeywordsSIGNALING PROTEIN / STRUCTURAL PROTEIN
Function / homology
Function and homology information


G protein-coupled enkephalin receptor activity / spine apparatus / positive regulation of CREB transcription factor activity / G protein-coupled opioid receptor activity / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / G protein-coupled opioid receptor signaling pathway / negative regulation of calcium ion-dependent exocytosis / G protein-coupled adenosine receptor signaling pathway / cellular response to toxic substance / negative regulation of adenylate cyclase activity ...G protein-coupled enkephalin receptor activity / spine apparatus / positive regulation of CREB transcription factor activity / G protein-coupled opioid receptor activity / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / G protein-coupled opioid receptor signaling pathway / negative regulation of calcium ion-dependent exocytosis / G protein-coupled adenosine receptor signaling pathway / cellular response to toxic substance / negative regulation of adenylate cyclase activity / positive regulation of urine volume / receptor serine/threonine kinase binding / positive regulation of neural precursor cell proliferation / negative regulation of synaptic transmission / neuropeptide binding / gamma-aminobutyric acid signaling pathway / eating behavior / neuronal dense core vesicle / negative regulation of apoptotic signaling pathway / regulation of calcium ion transport / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuropeptide signaling pathway / negative regulation of protein-containing complex assembly / Adenylate cyclase inhibitory pathway / positive regulation of peptidyl-serine phosphorylation / positive regulation of vascular associated smooth muscle cell proliferation / axon terminus / dendrite membrane / response to nutrient / hippocampal mossy fiber to CA3 synapse / Peptide ligand-binding receptors / regulation of mitochondrial membrane potential / adult locomotory behavior / positive regulation of superoxide anion generation / Regulation of insulin secretion / response to nicotine / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / postsynaptic density membrane / cellular response to growth factor stimulus / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / synaptic vesicle membrane / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / 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 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / presynaptic membrane / cell body / GTPase binding / Ca2+ pathway / retina development in camera-type eye / midbody / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / Interleukin-4 and Interleukin-13 signaling / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / cellular response to hypoxia / G alpha (q) signalling events / response to ethanol / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / positive regulation of ERK1 and ERK2 cascade
Similarity search - Function
Delta opioid receptor / Opioid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit ...Delta opioid receptor / Opioid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 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 / 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
: / Guanine nucleotide-binding protein G(i) subunit alpha-2 / Delta-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: 3.45 Å
AuthorsLin, C. / Chang, Z.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Cryo-EM structure of small-molecule agonist bound delta opioid receptor-G complex enables discovery of biased compound.
Authors: Lin Cheng / Zhuang Miao / Sicen Liu / Zhe Li / Hong Fu / Chanjuan Xu / Shilong Hu / Chang Zhao / Yuxuan Liu / Tiantian Zhao / Wencheng Liu / Heli Wang / Runduo Liu / Wei Yan / Xiangdong Tang ...Authors: Lin Cheng / Zhuang Miao / Sicen Liu / Zhe Li / Hong Fu / Chanjuan Xu / Shilong Hu / Chang Zhao / Yuxuan Liu / Tiantian Zhao / Wencheng Liu / Heli Wang / Runduo Liu / Wei Yan / Xiangdong Tang / Jianfeng Liu / Zhenhua Shao / Bowen Ke /
Abstract: Delta opioid receptor (δOR) plays a pivotal role in modulating human sensation and emotion. It is an attractive target for drug discovery since, unlike Mu opioid receptor, it is associated with low ...Delta opioid receptor (δOR) plays a pivotal role in modulating human sensation and emotion. It is an attractive target for drug discovery since, unlike Mu opioid receptor, it is associated with low risk of drug dependence. Despite its potential applications, the pharmacological properties of δOR, including the mechanisms of activation by small-molecule agonists and the complex signaling pathways it engages, as well as their relation to the potential side effects, remain poorly understood. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the δOR-G complex when bound to a small-molecule agonist (ADL5859). Moreover, we design a series of probes to examine the key receptor-ligand interaction site and identify a region involved in signaling bias. Using ADL06 as a chemical tool, we elucidate the relationship between the β-arrestin pathway of the δOR and its biological functions, such as analgesic tolerance and convulsion activities. Notably, we discover that the β-arrestin recruitment of δOR might be linked to reduced gastrointestinal motility. These insights enhance our understanding of δOR's structure, signaling pathways, and biological functions, paving the way for the structure-based drug discovery.
History
DepositionJan 30, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2024Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2024Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2024Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2024Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jun 18, 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
A: Delta-type opioid receptor
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(i) subunit alpha-2
S: scFv16
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,9176
Polymers152,5255
Non-polymers3921
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

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

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39336.020 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
#3: Protein Guanine nucleotide-binding protein G(i) subunit alpha-2 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40516.891 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI2, GNAI2B / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P04899
#5: 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 AS

#1: Protein Delta-type opioid receptor / D-OR-1 / DOR-1


Mass: 36173.980 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: OPRD1, OPRD / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41143
#4: Antibody scFv16


Mass: 28636.793 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-A1LXY / ~{N},~{N}-diethyl-4-(5-oxidanylspiro[chromene-2,4'-piperidine]-4-yl)benzamide


Mass: 392.491 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H28N2O3

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Cryo-EM structure of opioid receptor with biased agonist
Type: COMPLEX / Entity ID: #1-#2, #5, #3-#4 / Source: RECOMBINANT
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: PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Tecnai Spirit / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI SPIRIT
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 65 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 676428 / Symmetry type: POINT

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