7ZB6

Crystal Structure of SARS-CoV-2 Main Protease (Mpro) variant C44S at 2.12 A resolution

Summary for 7ZB6

• Entry DOI: 10.2210/pdb7zb6/pdb
• Descriptor: 3C-like proteinase nsp5, DIMETHYL SULFOXIDE (3 entities in total)
• Functional Keywords: sars-cov-2, mpro, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 67697.09

Authors

Paknia, E.,Rabe von Pappenheim, F.,Funk, L.-M.,Tittmann, K.,Chari, A. (deposition date: 2022-03-23, release date: 2022-06-01, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.12 Å)