7ZB8

Crystal Structure of SARS-CoV-2 Main Protease (Mpro) variant K61A at 2.48 A resolution

7ZB8 の概要

• エントリーDOI: 10.2210/pdb7zb8/pdb
• 分子名称: 3C-like proteinase nsp5, DIMETHYL SULFOXIDE (3 entities in total)
• 機能のキーワード: sars-cov-2, mpro, 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: 67847.41

構造登録者

Paknia, E.,Rabe von Pappenheim, F.,Funk, L.-M.,Tittmann, K.,Chari, A. (登録日: 2022-03-23, 公開日: 2022-06-01, 最終更新日: 2024-01-31)

主引用文献

Funk, L.M.,Poschmann, G.,Rabe von Pappenheim, F.,Chari, A.,Stegmann, K.M.,Dickmanns, A.,Wensien, M.,Eulig, N.,Paknia, E.,Heyne, G.,Penka, E.,Pearson, A.R.,Berndt, C.,Fritz, T.,Bazzi, S.,Uranga, J.,Mata, R.A.,Dobbelstein, M.,Hilgenfeld, R.,Curth, U.,Tittmann, K.
Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design.
Nat Commun, 15:411-411, 2024

PubMed Abstract: Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for preventing future COVID outbreaks. The SARS-CoV-2 main protease (M), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that M is subject to redox regulation in vitro and reversibly switches between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues. These include a disulfide-dithiol switch between the catalytic cysteine C145 and cysteine C117, and generation of an allosteric cysteine-lysine-cysteine SONOS bridge that is required for structural stability under oxidative stress conditions, such as those exerted by the innate immune system. We identify homo- and heterobifunctional reagents that mimic the redox switching and inhibit M activity. The discovered redox switches are conserved in main proteases from other coronaviruses, e.g. MERS-CoV and SARS-CoV, indicating their potential as common druggable sites.

PubMed: 38195625
DOI: 10.1038/s41467-023-44621-0

実験手法

X-RAY DIFFRACTION (2.48 Å)