8HZR

Crystal structure of SARS-Cov-2 main protease S46F mutant in complex with PF07321332

Summary for 8HZR

• Entry DOI: 10.2210/pdb8hzr/pdb
• Descriptor: 3C-like proteinase nsp5, (1R,2S,5S)-N-{(1E,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 66784.24

Authors

Zeng, X.Y.,Zhang, J.,Li, J. (deposition date: 2023-01-09, release date: 2024-01-17, Last modification date: 2025-07-09)

Primary citation

Jiang, H.,Zhou, Y.,Zou, X.,Hu, X.,Wang, J.,Zeng, P.,Li, W.,Zeng, X.,Zhang, J.,Li, J.
Evaluation of the Inhibition Potency of Nirmatrelvir against Main Protease Mutants of SARS-CoV-2 Variants.
Biochemistry, 62:2055-2064, 2023

PubMed Abstract: SARS-CoV-2 continues to pose a threat to public health. Main protease (M) is one of the most lucrative drug targets for developing specific antivirals against SARS-CoV-2 infection. By targeting M, peptidomimetic nirmatrelvir is able to inhibit viral replication of SARS-CoV-2 and reduce the risk for progression to severe COVID-19. However, multiple mutations in the gene encoding M of emerging SARS-CoV-2 variants raise a concern of drug resistance. In the present study, we expressed 16 previously reported SARS-CoV-2 M mutants (G15S, T25I, T45I, S46F, S46P, D48N, M49I, L50F, L89F, K90R, P132H, N142S, V186F, R188K, T190I, and A191V). We evaluated the inhibition potency of nirmatrelvir against these M mutants and solved the crystal structures of representative M mutants of SARS-CoV-2 bound to nirmatrelvir. Enzymatic inhibition assays revealed that these M variants remain susceptible to nirmatrelvir as the wildtype. Detailed analysis and structural comparison provided the inhibition mechanism of M mutants by nirmatrelvir. These results informed the ongoing genomic surveillance of drug resistance of emerging SARS-CoV-2 variants to nirmatrelvir and facilitate the development of next-generation anticoronavirus drugs.

PubMed: 37222536
DOI: 10.1021/acs.biochem.3c00075

Experimental method

X-RAY DIFFRACTION (1.92 Å)