6KD5

Crystal structure of the extracellular domain of MSPL/TMPRSS13 in complex with dec-RVKR-cmk inhibitor

Summary for 6KD5

• Entry DOI: 10.2210/pdb6kd5/pdb
• Descriptor: Transmembrane protease serine 13, DECANOYL-ARG-VAL-LYS-ARG-CHLOROMETHYLKETONE INHIBITOR, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: hydrolase, structural protein-inhibitor complex, structural protein/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 49190.20

Authors

Ohno, A.,Maita, N.,Okumura, Y.,Nikawa, T. (deposition date: 2019-06-30, release date: 2020-06-24, Last modification date: 2023-11-22)

Primary citation

Ohno, A.,Maita, N.,Tabata, T.,Nagano, H.,Arita, K.,Ariyoshi, M.,Uchida, T.,Nakao, R.,Ulla, A.,Sugiura, K.,Kishimoto, K.,Teshima-Kondo, S.,Okumura, Y.,Nikawa, T.
Crystal structure of inhibitor-bound human MSPL that can activate high pathogenic avian influenza.
Life Sci Alliance, 4:-, 2021

PubMed 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 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.

PubMed: 33820827
DOI: 10.26508/lsa.202000849

Experimental method

X-RAY DIFFRACTION (2.6 Å)