Structural basis of protease-activated receptor 2 activation and biased agonism.

ABSTRACT: Protease-activated receptor 2 (PAR2) is a transmembrane receptor that is irreversibly activated by proteolytic cleavage of its N-terminus via extracellular proteases, resulting in the release of the tethered ligand (TL), which binds to and activates the receptor. PAR2 plays a pivotal role in the inflammatory response and pain sensation and is a promising drug target for treating arthritis, asthma, and neuronal pain. Here, we present the cryo-electron microscopy structures of active PAR2 complexed with miniG_s/q and miniG₁₃. Combining functional assays with structural analysis, our study revealed that TL forms a parallel β-sheet with the extracellular loop 2 of PAR2 to engage the receptor. The binding of TL triggers a conformational rearrangement in the transmembrane co

SUBMITTER: Zhu X 

PROVIDER: S-EPMC12673148 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature