TY - JOUR T1 - Crystal structure of inhibitor-bound human MSPL that can activate high pathogenic avian influenza JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202000849 VL - 4 IS - 6 SP - e202000849 AU - Ayako Ohno AU - Nobuo Maita AU - Takanori Tabata AU - Hikaru Nagano AU - Kyohei Arita AU - Mariko Ariyoshi AU - Takayuki Uchida AU - Reiko Nakao AU - Anayt Ulla AU - Kosuke Sugiura AU - Koji Kishimoto AU - Shigetada Teshima-Kondo AU - Yuushi Okumura AU - Takeshi Nikawa Y1 - 2021/06/01 UR - https://www.life-science-alliance.org/content/4/6/e202000849.abstract N2 - Infection of certain influenza viruses is triggered when its HA is cleaved by host cell proteases such as proprotein convertases and type II transmembrane serine proteases (TTSP). HA with a monobasic motif is cleaved by trypsin-like proteases, including TMPRSS2 and HAT, whereas the multibasic motif found in high pathogenicity avian influenza HA is cleaved by furin, PC5/6, or MSPL. MSPL belongs to the TMPRSS family and preferentially cleaves [R/K]-K-K-R↓ sequences. Here, we solved the crystal structure of the extracellular region of human MSPL in complex with an irreversible substrate-analog inhibitor. The structure revealed three domains clustered around the C-terminal α-helix of the SPD. The inhibitor structure and its putative model show that the P1-Arg inserts into the S1 pocket, whereas the P2-Lys and P4-Arg interacts with the Asp/Glu-rich 99-loop that is unique to MSPL. Based on the structure of MSPL, we also constructed a homology model of TMPRSS2, which is essential for the activation of the SARS-CoV-2 spike protein and infection. The model may provide the structural insight for the drug development for COVID-19. ER -