8HUT

Crystal structure of MERS main protease in complex with S217622

Summary for 8HUT

• Entry DOI: 10.2210/pdb8hut/pdb
• Descriptor: ORF1a, 6-[(6-chloranyl-2-methyl-indazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[[2,4,5-tris(fluoranyl)phenyl]methyl]-1,3,5-triazine-2,4-dione (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein
• Biological source: Middle East respiratory syndrome-related coronavirus (MERS-CoV)
• Total number of polymer chains: 2
• Total formula weight: 66504.56

Authors

Lin, C.,Zhang, J.,Li, J. (deposition date: 2022-12-24, release date: 2023-06-21, Last modification date: 2024-02-07)

Primary citation

Lin, C.,Jiang, H.,Li, W.,Zeng, P.,Zhou, X.,Zhang, J.,Li, J.
Structural basis for the inhibition of coronaviral main proteases by ensitrelvir.
Structure, 31:1016-1024.e3, 2023

PubMed Abstract: Main protease (M) is a highly conserved cysteine protease that plays a vital role in the replication of coronaviruses, making it an attractive pan-coronaviral therapeutic target. Ensitrelvir (S-217622), developed by Shionogi, is the first orally active non-covalent, non-peptidic SARS-CoV-2 M inhibitor, which also displays antiviral efficacy against other human coronaviruses as well as SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs). Here, we report the crystal structures of the main proteases from SARS-CoV-2, SARS-CoV-2 VOC/VOIs, SARS-CoV, MERS-CoV, and HCoV-NL63 bound to the inhibitor S-217622. A detailed analysis of these structures illuminates key structural determinants essential for inhibition and elucidates the binding modes of the main proteases from different coronaviruses. Given the importance of the main protease for the treatment of coronaviral infection, structural insights obtained from this study could accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.

PubMed: 37421945
DOI: 10.1016/j.str.2023.06.010

Experimental method

X-RAY DIFFRACTION (1.98 Å)