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- PDB-9d4z: CryoEM structure of PAR1 with endogenous tethered ligand -

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Basic information

Entry
Database: PDB / ID: 9d4z
TitleCryoEM structure of PAR1 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 chimera
  • Proteinase-activated receptor 1
  • scFv16
KeywordsIMMUNE SYSTEM / PAR2 / endogenous ligand.
Function / homology
Function and homology information


negative regulation of renin secretion into blood stream / dendritic cell homeostasis / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / establishment of synaptic specificity at neuromuscular junction / platelet dense tubular network / thrombin-activated receptor activity / cell-cell junction maintenance / regulation of interleukin-1 beta production / connective tissue replacement involved in inflammatory response wound healing / platelet dense granule organization ...negative regulation of renin secretion into blood stream / dendritic cell homeostasis / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / establishment of synaptic specificity at neuromuscular junction / platelet dense tubular network / thrombin-activated receptor activity / cell-cell junction maintenance / regulation of interleukin-1 beta production / connective tissue replacement involved in inflammatory response wound healing / platelet dense granule organization / regulation of sensory perception of pain / positive regulation of smooth muscle contraction / positive regulation of calcium ion transport / negative regulation of glomerular filtration / thrombin-activated receptor signaling pathway / positive regulation of Rho protein signal transduction / regulation of blood coagulation / positive regulation of collagen biosynthetic process / anatomical structure morphogenesis / positive regulation of blood coagulation / G-protein alpha-subunit binding / Common Pathway of Fibrin Clot Formation / homeostasis of number of cells within a tissue / positive regulation of vasoconstriction / release of sequestered calcium ion into cytosol / positive regulation of GTPase activity / positive regulation of release of sequestered calcium ion into cytosol / Peptide ligand-binding receptors / positive regulation of interleukin-8 production / positive regulation of receptor signaling pathway via JAK-STAT / G protein-coupled receptor activity / neuromuscular junction / regulation of synaptic plasticity / caveola / platelet activation / positive regulation of interleukin-6 production / response to wounding / 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 / G-protein activation / 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 / late endosome / 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) / GTPase binding / positive regulation of cytosolic calcium ion concentration / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / negative regulation of neuron apoptotic process / response to lipopolysaccharide / postsynaptic membrane / Ras protein signal transduction / positive regulation of canonical NF-kappaB signal transduction / early endosome / Extra-nuclear estrogen signaling / cell population proliferation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / positive regulation of cell migration / G protein-coupled receptor signaling pathway / positive regulation of apoptotic process
Similarity search - Function
Thrombin receptor / Protease-activated receptor / 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 ...Thrombin receptor / Protease-activated receptor / 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
Similarity search - Domain/homology
Proteinase-activated receptor 1 / 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: 2.74 Å
AuthorsLyu, X. / Lyu, Z. / 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 13, 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 14, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 14, 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
R: Proteinase-activated receptor 1
E: scFv16
A: Guanine nucleotide-binding protein G(q) subunit alpha chimera


Theoretical massNumber of molelcules
Total (without water)155,4635
Polymers155,4635
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: Protein Proteinase-activated receptor 1 / PAR-1 / Coagulation factor II receptor / Thrombin receptor


Mass: 43020.996 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2R, CF2R, PAR1, TR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P25116
#4: Antibody scFv16


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)
#5: Protein Guanine nucleotide-binding protein G(q) subunit alpha chimera


Mass: 41972.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
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 PAR1 with G proteins / Type: COMPLEX / Entity ID: #3, #1-#2, #4-#5 / 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: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1904551 / Symmetry type: POINT
RefinementHighest resolution: 2.74 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048463
ELECTRON MICROSCOPYf_angle_d0.58311497
ELECTRON MICROSCOPYf_dihedral_angle_d4.9861158
ELECTRON MICROSCOPYf_chiral_restr0.0421313
ELECTRON MICROSCOPYf_plane_restr0.0041445

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