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Publication Abstract from PubMed

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.

Structural basis for the activation of proteinase-activated receptors PAR1 and PAR2.,Lyu Z, Lyu X, Malyutin AG, Xia G, Carney D, Alves VM, Falk M, Arora N, Zou H, McGrath AP, Kang Y Nat Commun. 2025 Apr 26;16(1):3931. doi: 10.1038/s41467-025-59138-x. PMID:40287415^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.