8DGB

Crystal Structure of SARS-CoV-2 Main Protease (Mpro) Q192T Mutant in Complex with Inhibitor GC376

Summary for 8DGB

• Entry DOI: 10.2210/pdb8dgb/pdb
• Descriptor: 3C-like proteinase nsp5, (1R,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 Keywords: protease, sars-cov-2, mpro, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 68568.14

Authors

Lewandowski, E.M.,Jacobs, L.M.C.,Hu, Y.,Tan, H.,Wang, J.,Chen, Y. (deposition date: 2022-06-23, release date: 2022-07-13, Last modification date: 2023-10-25)

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.
Acs Cent.Sci., 9:1658-1669, 2023

PubMed Abstract: The SARS-CoV-2 main protease (M) is the drug target of Pfizer's oral drug nirmatrelvir. The emergence of SARS-CoV-2 variants with mutations in M raised the alarm of potential drug resistance. To identify potential clinically relevant drug-resistant mutants, we systematically characterized 102 naturally occurring M mutants located at 12 residues at the nirmatrelvir-binding site, among which 22 mutations in 5 residues, including S144M/F/A/G/Y, M165T, E166 V/G/A, H172Q/F, and Q192T/S/L/A/I/P/H/V/W/C/F, showed comparable enzymatic activity to the wild-type (/ < 10-fold change) while being resistant to nirmatrelvir ( > 10-fold increase). X-ray crystal structures were determined for six representative mutants with and/or without GC-376/nirmatrelvir. Using recombinant SARS-CoV-2 viruses generated from reverse genetics, we confirmed the drug resistance in the antiviral assay and showed that M mutants with reduced enzymatic activity had attenuated viral replication. Overall, our study identified several drug-resistant hotspots in M that warrant close monitoring for possible clinical evidence of nirmatrelvir resistance, some of which have already emerged in independent viral passage assays conducted by others.

PubMed: 37637734
DOI: 10.1021/acscentsci.3c00538

Experimental method

X-RAY DIFFRACTION (2.87 Å)