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- PDB-9d0a: CryoEM structure of PAR2 with endogenous tethered ligand. -

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Basic information

Entry
Database: PDB / ID: 9d0a
TitleCryoEM structure of PAR2 with endogenous tethered ligand.
Components
  • 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
  • Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short chimera,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
  • Proteinase-activated receptor 2
  • scFv16
KeywordsIMMUNE SYSTEM / PAR2 / endogenous ligand
Function / homology
Function and homology information


positive regulation of neutrophil mediated killing of gram-negative bacterium / positive regulation of renin secretion into blood stream / positive regulation of eosinophil degranulation / mature conventional dendritic cell differentiation / leukocyte proliferation / positive regulation of glomerular filtration / regulation of chemokine (C-X-C motif) ligand 2 production / negative regulation of toll-like receptor 3 signaling pathway / positive regulation of toll-like receptor 3 signaling pathway / thrombin-activated receptor activity ...positive regulation of neutrophil mediated killing of gram-negative bacterium / positive regulation of renin secretion into blood stream / positive regulation of eosinophil degranulation / mature conventional dendritic cell differentiation / leukocyte proliferation / positive regulation of glomerular filtration / regulation of chemokine (C-X-C motif) ligand 2 production / negative regulation of toll-like receptor 3 signaling pathway / positive regulation of toll-like receptor 3 signaling pathway / thrombin-activated receptor activity / positive regulation of toll-like receptor 2 signaling pathway / positive regulation of actin filament depolymerization / cell-cell junction maintenance / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / positive regulation of toll-like receptor 4 signaling pathway / positive regulation of pseudopodium assembly / phospholipase C-activating serotonin receptor signaling pathway / T cell activation involved in immune response / PLC beta mediated events / positive regulation of cytokine production involved in immune response / regulation of platelet activation / entrainment of circadian clock / positive regulation of phagocytosis, engulfment / negative regulation of chemokine production / neutrophil activation / positive regulation of chemotaxis / positive regulation of leukocyte chemotaxis / establishment of endothelial barrier / positive regulation of positive chemotaxis / regulation of JNK cascade / regulation of canonical NF-kappaB signal transduction / regulation of canonical Wnt signaling pathway / negative regulation of JNK cascade / leukocyte migration / glutamate receptor signaling pathway / positive regulation of Rho protein signal transduction / regulation of blood coagulation / pseudopodium / positive regulation of interleukin-10 production / PKA activation in glucagon signalling / phototransduction, visible light / positive regulation of GTPase activity / developmental growth / G-protein alpha-subunit binding / hair follicle placode formation / photoreceptor outer segment / negative regulation of tumor necrosis factor-mediated signaling pathway / neuropeptide signaling pathway / D1 dopamine receptor binding / postsynaptic cytosol / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / positive regulation of chemokine production / positive regulation of superoxide anion generation / adenylate cyclase-activating adrenergic receptor signaling pathway / enzyme regulator activity / response to prostaglandin E / cellular response to glucagon stimulus / regulation of insulin secretion / GTPase activator activity / Peptide ligand-binding receptors / adenylate cyclase activator activity / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / positive regulation of interleukin-8 production / positive regulation of JNK cascade / negative regulation of inflammatory response to antigenic stimulus / negative regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / bone development / positive regulation of interleukin-6 production / platelet aggregation / G-protein beta/gamma-subunit complex binding / vasodilation / cognition / Olfactory Signaling Pathway / positive regulation of type II interferon production / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / blood coagulation / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12
Similarity search - Function
Protease-activated receptor 2 / Protease-activated receptor / G-protein alpha subunit, group Q / G-protein alpha subunit, group S / 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 ...Protease-activated receptor 2 / Protease-activated receptor / G-protein alpha subunit, group Q / G-protein alpha subunit, group S / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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. / 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(q) subunit alpha / Proteinase-activated receptor 2 / 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 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
unidentified (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsLyu, Z. / Lyu, X. / McGrath, A.P. / Kang, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis for the activation of proteinase-activated receptors PAR1 and PAR2.
Authors: Zongyang Lyu / Xiaoxuan Lyu / Andrey G Malyutin / Guliang Xia / Daniel Carney / Vinicius M Alves / Matthew Falk / Nidhi Arora / Hua Zou / Aaron P McGrath / Yanyong Kang /
Abstract: Members of the proteinase-activated receptor (PAR) subfamily of G protein-coupled receptors (GPCRs) play critical roles in processes like hemostasis, thrombosis, development, wound healing, ...Members of the proteinase-activated receptor (PAR) subfamily of G protein-coupled receptors (GPCRs) play critical roles in processes like hemostasis, thrombosis, development, wound healing, inflammation, and cancer progression. Comprising PAR1-PAR4, these receptors are specifically activated by protease cleavage at their extracellular amino terminus, revealing a 'tethered ligand' that self-activates the receptor. This triggers complex intracellular signaling via G proteins and beta-arrestins, linking external protease signals to cellular functions. To date, direct structural visualization of these ligand-receptor complexes has been limited. Here, we present structural snapshots of activated PAR1 and PAR2 bound to their endogenous tethered ligands, revealing a shallow and constricted orthosteric binding pocket. Comparisons with antagonist-bound structures show minimal conformational changes in the TM6 helix and larger movements of TM7 upon activation. These findings reveal a common activation mechanism for PAR1 and PAR2, highlighting critical residues involved in ligand recognition. Additionally, the structure of PAR2 bound to a pathway selective antagonist, GB88, demonstrates how potent orthosteric engagement can be achieved by a small molecule mimicking the endogenous tethered ligand's interactions.
History
DepositionAug 6, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 7, 2025Provider: repository / Type: Initial release
Revision 1.0May 7, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 7, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0May 7, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 7, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 7, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 7, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1May 28, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 28, 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
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: scFv16
R: Proteinase-activated receptor 2
A: Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short chimera,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short


Theoretical massNumber of molelcules
Total (without water)156,6165
Polymers156,6165
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: 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
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 6504.446 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
#3: Antibody scFv16


Mass: 26679.721 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) unidentified (others) / Production host: Spodoptera frugiperda (fall armyworm)
#4: Protein Proteinase-activated receptor 2 / PAR-2 / Coagulation factor II receptor-like 1 / G-protein coupled receptor 11 / Thrombin receptor-like 1


Mass: 44173.203 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2RL1, GPR11, PAR2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P55085
#5: Protein Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short chimera,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein alpha-q / Adenylate cyclase-stimulating G alpha protein


Mass: 41972.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAQ, GAQ, GNAS, GNAS1, GSP / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P50148, UniProt: P63092
Has ligand of interestN
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: Complex of PAR2 with G proteins / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 45 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 404635 / Symmetry type: POINT
RefinementHighest resolution: 3.1 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038611
ELECTRON MICROSCOPYf_angle_d0.5311690
ELECTRON MICROSCOPYf_dihedral_angle_d5.0511173
ELECTRON MICROSCOPYf_chiral_restr0.041330
ELECTRON MICROSCOPYf_plane_restr0.0041471

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