Structural basis for the activation of proteinase-activated receptors PAR1 and PAR2
Zongyang Lyu, Xiaoxuan Lyu, Andrey Malyutin, Guliang Xia, Daniel W. Carney, Vinícius M. Alves, Matthew S. 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, 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. Proteinase-activated receptors (PARs) regulate thrombosis, inflammation, and wound healing. Here, authors present PAR1 and PAR2 structures, revealing conserved activation mechanisms and ligand interactions within their orthosteric pockets, providing insights into PAR functionality.