A KLK4 proteinase substrate capture approach to antagonize PAR1.

ABSTRACT: Proteinase-activated receptor-1 (PAR1), triggered by thrombin and other serine proteinases such as tissue kallikrein-4 (KLK4), is a key driver of inflammation, tumor invasiveness and tumor metastasis. The PAR1 transmembrane G-protein-coupled receptor therefore represents an attractive target for therapeutic inhibitors. We thus used a computational design to develop a new PAR1 antagonist, namely, a catalytically inactive human KLK4 that acts as a proteinase substrate-capture reagent, preventing receptor cleavage (and hence activation) by binding to and occluding the extracellular R41-S42 canonical PAR1 proteolytic activation site. On the basis of in silico site-saturation mutagenesis, we then generated KLK4_S207A,L185D, a first-of-a-kind 'decoy' PAR1 inhibitor, by mutating the S20

SUBMITTER: Rabinovitch E 

PROVIDER: S-EPMC8352894 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature