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 Ohno, Ayako
A1 Maita, Nobuo
A1 Tabata, Takanori
A1 Nagano, Hikaru
A1 Arita, Kyohei
A1 Ariyoshi, Mariko
A1 Uchida, Takayuki
A1 Nakao, Reiko
A1 Ulla, Anayt
A1 Sugiura, Kosuke
A1 Kishimoto, Koji
A1 Teshima-Kondo, Shigetada
A1 Okumura, Yuushi
A1 Nikawa, Takeshi
YR 2021
UL http://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.