8D4J

Crystal Structure of SARS-CoV-2 Main Protease (Mpro) H172Y Mutant

Summary for 8D4J

• Entry DOI: 10.2210/pdb8d4j/pdb
• Related: 8D4K 8D4L 8D4M 8D4N
• Descriptor: 3C-like proteinase nsp5, GLYCEROL (3 entities in total)
• Functional Keywords: protease, sars-cov-2, mpro, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 67793.24

Authors

Lewandowski, E.M.,Hu, Y.,Tan, H.,Wang, J.,Chen, Y. (deposition date: 2022-06-02, release date: 2022-07-13, Last modification date: 2023-10-18)

Primary citation

Hu, Y.,Lewandowski, E.M.,Tan, H.,Zhang, X.,Morgan, R.T.,Zhang, X.,Jacobs, L.M.C.,Butler, S.G.,Gongora, M.V.,Choy, J.,Deng, X.,Chen, Y.,Wang, J.
Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir.
Biorxiv, 2022

PubMed Abstract: The SARS-CoV-2 main protease (M ) is the drug target of Pfizer’s oral drug Paxlovid. The emergence of SARS-CoV-2 variants with mutations in M raised the alarm of potential drug resistance. In this study, we identified 100 naturally occurring M mutations located at the nirmatrelvir binding site, among which 20 mutants, including S144M/F/A/G/Y, M165T, E166G, H172Q/F, and Q192T/S/L/A/I/P/H/V/W/C/F, showed comparable enzymatic activity to the wild-type (k /K <10-fold change) and resistance to nirmatrelvir (K >10-fold increase). X-ray crystal structures were determined for seven representative mutants with and/or without GC-376/nirmatrelvir. Viral growth assay showed that M mutants with reduced enzymatic activity led to attenuated viral replication. Overall, our study identified several drug resistant hot spots that warrant close monitoring for possible clinical evidence of Paxlovid resistance.

PubMed: 36119652
DOI: 10.1101/2022.06.28.497978

Experimental method

X-RAY DIFFRACTION (1.78 Å)