7UUD

Structure of the SARS-CoV-2 main protease in complex with inhibitor MPI33

Summary for 7UUD

• Entry DOI: 10.2210/pdb7uud/pdb
• Descriptor: 3C-like proteinase nsp5, (1R,2S,5S)-3-[N-(tert-butylcarbamoyl)-3-methyl-L-valyl]-N-{(2S,3R)-4-(ethylamino)-3-hydroxy-4-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (3 entities in total)
• Functional Keywords: main protease, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2, COVID-19 virus)
• Total number of polymer chains: 1
• Total formula weight: 34436.29

Authors

Yang, K.S.,Liu, W.R. (deposition date: 2022-04-28, release date: 2023-01-25, Last modification date: 2024-10-23)

Primary citation

Yang, K.S.,Blankenship, L.R.,Kuo, S.A.,Sheng, Y.J.,Li, P.,Fierke, C.A.,Russell, D.H.,Yan, X.,Xu, S.,Liu, W.R.
A Novel Y-Shaped, S-O-N-O-S-Bridged Cross-Link between Three Residues C22, C44, and K61 Is Frequently Observed in the SARS-CoV-2 Main Protease.
Acs Chem.Biol., 18:449-455, 2023

PubMed Abstract: As the COVID-19 pathogen, SARS-CoV-2 relies on its main protease (M) for pathogenesis and replication. During crystallographic analyses of M crystals that were exposed to the air, a uniquely Y-shaped, S-O-N-O-S-bridged post-translational cross-link that connects three residues C22, C44, and K61 at their side chains was frequently observed. As a novel covalent modification, this cross-link serves potentially as a redox switch to regulate the catalytic activity of M, a demonstrated drug target of COVID-19. The formation of this linkage leads to a much more open active site that can potentially be targeted for the development of novel SARS-CoV-2 antivirals. The structural rearrangement of M by this cross-link indicates that small molecules that lock M in the cross-linked form can potentially be used with other active-site-targeting molecules such as paxlovid for synergistic effects in inhibiting SARS-CoV-2 viral replication.

PubMed: 36629751
DOI: 10.1021/acschembio.2c00695

Experimental method

X-RAY DIFFRACTION (1.85 Å)