RT Journal Article
SR Electronic
T1 Crystal structure of inhibitor-bound human MSPL that can activate high pathogenic avian influenza
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000849
DO 10.26508/lsa.202000849
VO 4
IS 6
A1 Ayako Ohno
A1 Nobuo Maita
A1 Takanori Tabata
A1 Hikaru Nagano
A1 Kyohei Arita
A1 Mariko Ariyoshi
A1 Takayuki Uchida
A1 Reiko Nakao
A1 Anayt Ulla
A1 Kosuke Sugiura
A1 Koji Kishimoto
A1 Shigetada Teshima-Kondo
A1 Yuushi Okumura
A1 Takeshi Nikawa
YR 2021
UL https://www.life-science-alliance.org/content/4/6/e202000849.abstract
AB 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.