Unravelling Structure‐Based Molecular Activation and Antagonism of Protease‐Activated Receptors for Drug Design

Protease-activated receptors (PARs) are G protein-coupled receptors (GPCRs) characterized by their self-activation following cleavage by specific proteases, serving as vital therapeutic targets for cardiovascular and inflammatory diseases. The breakthroughs in structural biology have enabled the structure determination of PARs in complex with orthosteric ligands and allosteric modulators, which provides valuable information for the rational design of PAR-targeted drugs. Herein, we comprehensively summarize the reported PAR modulators and clinical candidates, as well as the available PAR structures, particularly the recognition patterns of different ligands including agonists, antagonist, negative allosteric modulators and blocking antibody. Furthermore, the activation and antagonism mechanisms of PARs are shown. Finally, we discuss the contribution of PAR structures to drug design. This study will promote the structure-based drug discovery for therapeutics targeting PARs.