Crystal structure of inhibitor-bound human MSPL that can activate high pathogenic avian influenza

Infection of certain influenza viruses is triggered when its HA cleaved by host cell proteases such as proprotein convertases and type II transmembrane serine (TTSP). with a monobasic motif trypsin-like proteases, including TMPRSS2 HAT, whereas the multibasic found in high pathogenicity avian furin, PC5/6, or MSPL. MSPL belongs to TMPRSS family preferentially cleaves [R/K]-K-K-R↓ sequences. Here, we solved crystal structure extracellular region human complex an irreversible substrate-analog inhibitor. The revealed three domains clustered around C-terminal α-helix SPD. inhibitor putative model show that P1-Arg inserts into S1 pocket, P2-Lys P4-Arg interacts Asp/Glu-rich 99-loop unique Based on MSPL, also constructed homology TMPRSS2, which essential for activation SARS-CoV-2 spike protein infection. may provide structural insight drug development COVID-19.