8SG6

SARS-CoV-2 Main Protease (Mpro) H163A Mutant Reduced with 20mM TCEP

8SG6 の概要

• エントリーDOI: 10.2210/pdb8sg6/pdb
• 関連するPDBエントリー: 8DD6 8DDL
• 分子名称: 3C-like proteinase nsp5, GLYCEROL (3 entities in total)
• 機能のキーワード: cysteine protease, sars-cov-2, 3cl-like, disulfide bond, viral protein, hydrolase
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67609.05

構造登録者

Tran, N.,McLeod, M.J.,Barwell, S.,Kalyaanamoorthy, S.,Ganesan, A.,Holyoak, T. (登録日: 2023-04-11, 公開日: 2023-09-27)

主引用文献

Tran, N.,Dasari, S.,Barwell, S.A.E.,McLeod, M.J.,Kalyaanamoorthy, S.,Holyoak, T.,Ganesan, A.
The H163A mutation unravels an oxidized conformation of the SARS-CoV-2 main protease.
Nat Commun, 14:5625-5625, 2023

PubMed Abstract: The main protease of SARS-CoV-2 (Mpro) is an important target for developing COVID-19 therapeutics. Recent work has highlighted Mpro's susceptibility to undergo redox-associated conformational changes in response to cellular and immune-system-induced oxidation. Despite structural evidence indicating large-scale rearrangements upon oxidation, the mechanisms of conformational change and its functional consequences are poorly understood. Here, we present the crystal structure of an Mpro point mutant (H163A) that shows an oxidized conformation with the catalytic cysteine in a disulfide bond. We hypothesize that Mpro adopts this conformation under oxidative stress to protect against over-oxidation. Our metadynamics simulations illustrate a potential mechanism by which H163 modulates this transition and suggest that this equilibrium exists in the wild type enzyme. We show that other point mutations also significantly shift the equilibrium towards this state by altering conformational free energies. Unique avenues of SARS-CoV-2 research can be explored by understanding how H163 modulates this equilibrium.

PubMed: 37699927
DOI: 10.1038/s41467-023-40023-4

実験手法

X-RAY DIFFRACTION (2.49 Å)