8INY

Crystal Structure of SARS-CoV-2 Main Protease (Mpro) K90R Mutant in Complex with Inhibitor ensitrelvir

Summary for 8INY

• Entry DOI: 10.2210/pdb8iny/pdb
• Descriptor: 3C-like proteinase, 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: sars-cov-2, mutant, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34385.44

Authors

Lin, M.,Liu, X. (deposition date: 2023-03-10, release date: 2024-03-13, Last modification date: 2025-04-09)

Primary citation

Lin, M.,Zeng, X.,Duan, Y.,Yang, Z.,Ma, Y.,Yang, H.,Yang, X.,Liu, X.
Molecular mechanism of ensitrelvir inhibiting SARS-CoV-2 main protease and its variants.
Commun Biol, 6:694-694, 2023

PubMed Abstract: SARS-CoV-2 poses an unprecedented threat to the world as the causative agent of the COVID-19 pandemic. Among a handful of therapeutics developed for the prevention and treatment of SARS-CoV-2 infection, ensitrelvir is the first noncovalent and nonpeptide oral inhibitor targeting the main protease (M) of SARS-CoV-2, which recently received emergency regulatory approval in Japan. Here we determined a 1.8-Å structure of M in complex with ensitrelvir, which revealed that ensitrelvir targets the substrate-binding pocket of M, specifically recognizing its S1, S2, and S1' subsites. Further, our comprehensive biochemical and structural data have demonstrated that even though ensitrelvir and nirmatrelvir (an FDA-approved drug) belong to different types of M inhibitors, both of them remain to be effective against Ms from all five SARS-CoV-2 variants of concern, suggesting M is a bona fide broad-spectrum target. The molecular mechanisms uncovered in this study provide basis for future inhibitor design.

PubMed: 37407698
DOI: 10.1038/s42003-023-05071-y

Experimental method

X-RAY DIFFRACTION (1.59 Å)