8D4K

Crystal Structure of SARS-CoV-2 Main Protease (Mpro) H172Y Mutant in Complex with Inhibitor GC376

8D4K の概要

• エントリーDOI: 10.2210/pdb8d4k/pdb
• 関連するPDBエントリー: 8D4J 8D4L 8D4M 8D4N
• 関連するBIRD辞書のPRD_ID: PRD_002495
• 分子名称: 3C-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)
• 機能のキーワード: protease, sars-cov-2, mpro, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34336.13

構造登録者

Lewandowski, E.M.,Hu, Y.,Tan, H.,Wang, J.,Chen, Y. (登録日: 2022-06-02, 公開日: 2022-07-13, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.89 Å)