8K6C

Crystal structure of SARS-CoV-2 3CLpro M49K/S301P mutant

Summary for 8K6C

• Entry DOI: 10.2210/pdb8k6c/pdb
• Descriptor: 3C-like proteinase nsp5 (2 entities in total)
• Functional Keywords: sars-cov-2 3clpro, mutant, wu-04, inhibitor, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 67667.13

Authors

Zhang, L.J.,Hu, Q. (deposition date: 2023-07-25, release date: 2024-06-05)

Primary citation

Zhang, L.,Xie, X.,Luo, H.,Qian, R.,Yang, Y.,Yu, H.,Huang, J.,Shi, P.Y.,Hu, Q.
Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04.
Cell Discov, 10:40-40, 2024

PubMed Abstract: Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04, which is currently in phase III clinical trials (NCT06197217). Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04-binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates. The M165V mutation directly interferes with WU-04 binding. The S301P mutation, which is far from the WU-04-binding pocket, indirectly affects WU-04 binding by restricting the rotation of 3CLpro's C-terminal tail and impeding 3CLpro dimerization. We further explored 3CLpro mutations that confer resistance to two clinically used inhibitors: ensitrelvir and nirmatrelvir, and revealed a trade-off between the catalytic activity, thermostability, and drug resistance of 3CLpro. We found that mutations at the same residue (M49) can have distinct effects on the 3CLpro inhibitors, highlighting the importance of developing multiple antiviral agents with different skeletons for fighting SARS-CoV-2. These findings enhance our understanding of SARS-CoV-2 resistance mechanisms and inform the development of effective therapeutics.

PubMed: 38594245
DOI: 10.1038/s41421-024-00673-0

Experimental method

X-RAY DIFFRACTION (2.21 Å)