ArticleNature communications2025
Structural basis for the activation of proteinase-activated receptors PAR1 and PAR2.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
What it found
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Who cites it
14 citing papers in PubMed.
- Marine-Derived Proteins: Individual Variability in Health Effects Across Protein Structure, Host Genetics, and Gut Microbiota.Comprehensive reviews in food science and food safety · 2026Review
- Protease-Activated Receptor-2 as a Proteolytic Rheostat in Colorectal and Pancreatic Cancer: From Mechanism to Biomarker-Guided Therapy.International journal of molecular sciences · 2026Review
- Proteinase-Activated Receptor 2 (PAR2) Deficiency and Cardiovascular Regulation: Context-Dependent Effects on Inflammation and Fibrosis.Current issues in molecular biology · 2026Review
- Gastrointestinal Fate and Receptor-Mediated Mechanism of GPSGPQGSR, an Intestinal Barrier-Protective Collagen Peptide from ALASKA Pollock Skin.Marine drugs · 2026Article
- Protease-Activated Receptor-2 Promotes Metastasis: An Emerging Therapeutic Target.Molecular cancer research : MCR · 2026Review
- Signaling bias of the protease-activated receptor-1 is dictated by distinct GRK5 and β-arrestin-2 determinants.Cell reports · 2026Article
- Pan-cancer immunogenomics and structure-guided repurposing identify N-Acetyl-L-carnosine as a PAR2 binding modulator.Inflammopharmacology · 2026Article
- Activated protein C drives β-arrestin-2- and c-Src-dependent phosphorylation of Cav1 and modulates Cav1 association with PAR1 and GRK5.The Journal of biological chemistry · 2026Article
- Constitutive activity among orphan G protein-coupled receptors: Molecular mechanisms and pharmacological perspectives.Molecular pharmacology · 2026Review
- Bisphenols-enhanced platelet aggregation via TP, P2YFrontiers in pharmacology · 2026Article
- Reframing ATR: from the immunologic/nonimmunologic dichotomy to adaptive, innate, and physicochemical drivers within the allergy-inflammation-coagulation axis.Frontiers in immunology · 2026Review
- Structural basis of protease-activated receptor 2 activation and biased agonism.Cell discovery · 2025Article
- Article
- Constitutively active orphan G protein-coupled receptors through the lenses of cryo-electron microscopy.The Journal of biological chemistry · 2025Review
Corrections and comments
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
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, 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.