tetano
Editor, Senior Moderator
Life Sci Alliance
. 2021 Apr 5;4(6):e202000849.
doi: 10.26508/lsa.202000849. Print 2021 Jun.
Crystal structure of inhibitor-bound human MSPL that can activate high pathogenic avian influenza
Ayako Ohno[SUP] 1 [/SUP], Nobuo Maita[SUP] 2 [/SUP], Takanori Tabata[SUP] 3 [/SUP], Hikaru Nagano[SUP] 4 [/SUP], Kyohei Arita[SUP] 5 [/SUP], Mariko Ariyoshi[SUP] 6 [/SUP], Takayuki Uchida[SUP] 1 [/SUP], Reiko Nakao[SUP] 1 [/SUP], Anayt Ulla[SUP] 1 [/SUP], Kosuke Sugiura[SUP] 1 7 [/SUP], Koji Kishimoto[SUP] 8 [/SUP], Shigetada Teshima-Kondo[SUP] 4 [/SUP], Yuushi Okumura[SUP] 9 [/SUP], Takeshi Nikawa[SUP] 1 [/SUP]
Affiliations
Abstract
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 ?-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.
. 2021 Apr 5;4(6):e202000849.
doi: 10.26508/lsa.202000849. Print 2021 Jun.
Crystal structure of inhibitor-bound human MSPL that can activate high pathogenic avian influenza
Ayako Ohno[SUP] 1 [/SUP], Nobuo Maita[SUP] 2 [/SUP], Takanori Tabata[SUP] 3 [/SUP], Hikaru Nagano[SUP] 4 [/SUP], Kyohei Arita[SUP] 5 [/SUP], Mariko Ariyoshi[SUP] 6 [/SUP], Takayuki Uchida[SUP] 1 [/SUP], Reiko Nakao[SUP] 1 [/SUP], Anayt Ulla[SUP] 1 [/SUP], Kosuke Sugiura[SUP] 1 7 [/SUP], Koji Kishimoto[SUP] 8 [/SUP], Shigetada Teshima-Kondo[SUP] 4 [/SUP], Yuushi Okumura[SUP] 9 [/SUP], Takeshi Nikawa[SUP] 1 [/SUP]
Affiliations
- PMID: 33820827
- DOI: 10.26508/lsa.202000849
Abstract
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 ?-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.