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8D4M

Crystal Structure of SARS-CoV-2 Main Protease (Mpro) S144A Mutant in Complex with Inhibitor GC376

Summary for 8D4M
Entry DOI10.2210/pdb8d4m/pdb
Related8D4J 8D4K 8D4L 8D4N
Related PRD IDPRD_002495
Descriptor3C-like proteinase nsp5, (1S,2S)-2-({N-[(benzyloxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid (3 entities in total)
Functional Keywordsprotease, sars-cov-2, mpro, viral protein
Biological sourceSevere acute respiratory syndrome coronavirus 2
Total number of polymer chains1
Total formula weight34295.10
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: 2024-10-23)
Primary citationHu, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.81 Å)
Structure validation

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