Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition.

ABSTRACT: Protease-activated receptor-2 (PAR2) has been implicated in multiple pathophysiologies but drug discovery is challenging due to low small molecule tractability and a complex activation mechanism. Here we report the pharmacological profiling of a potent new agonist, suggested by molecular modelling to bind in the putative orthosteric site, and two novel PAR2 antagonists with distinctly different mechanisms of inhibition. We identify coupling between different PAR2 binding sites. One antagonist is a competitive inhibitor that binds to the orthosteric site, while a second antagonist is a negative allosteric modulator that binds at a remote site. The allosteric modulator shows probe dependence, more effectively inhibiting peptide than protease activation of PAR2 signalling. Importantly, both a

SUBMITTER: Kennedy AJ 

PROVIDER: S-EPMC7747594 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature