<p>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 core, releasing the inhibitory ion lock and allowing receptor activation. Furthermore, we provide structural insights into the engagement of G_q and G₁₃ with PAR2, highlighting that a hydrophobic interaction mediated by the last methionine residue of Gα₁₃ is crucial for G₁₃ coupling selectivity. In combination with molecular dynamics simulations and mutagenesis, we identified the I39^TL3/D62^N-term interaction at the pocket side of the receptor as a key determinant of G₁₃ signaling. Disrupting this interaction significantly inhibits G₁₃ signaling while preserving G_q activity, enabling us to design a biased peptide ligand that selectively activates G_q signaling. The information revealed in this study provides a framework for understanding PAR2 signaling and offers a rational basis for the design of biased PAR2 ligands.</p>