7WYM

Structure of the SARS-COV-2 main protease with 337 inhibitor

Summary for 7WYM

• Entry DOI: 10.2210/pdb7wym/pdb
• Descriptor: 3C-like proteinase nsp5, N-methyl-N-[[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]prop-2-enamide (3 entities in total)
• Functional Keywords: structure of the sars-cov-2 main protease with 337 inhibitor, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34075.79

Authors

Qin, B.,Hou, P.,Gao, X.,Cui, S. (deposition date: 2022-02-16, release date: 2022-06-22, Last modification date: 2023-11-29)

Primary citation

Qin, B.,Craven, G.B.,Hou, P.,Chesti, J.,Lu, X.,Child, E.S.,Morgan, R.M.L.,Niu, W.,Zhao, L.,Armstrong, A.,Mann, D.J.,Cui, S.
Acrylamide fragment inhibitors that induce unprecedented conformational distortions in enterovirus 71 3C and SARS-CoV-2 main protease.
Acta Pharm Sin B, 12:3924-3933, 2022

PubMed Abstract: RNA viruses are critically dependent upon virally encoded proteases to cleave the viral polyproteins into functional proteins. Many of these proteases exhibit a similar fold and contain an essential catalytic cysteine, offering the opportunity to inhibit these enzymes with electrophilic small molecules. Here we describe the successful application of quantitative irreversible tethering (qIT) to identify acrylamide fragments that target the active site cysteine of the 3C protease (3C) of Enterovirus 71, the causative agent of hand, foot and mouth disease in humans, altering the substrate binding region. Further, we re-purpose these hits towards the main protease (M) of SARS-CoV-2 which shares the 3C-like fold and a similar active site. The hit fragments covalently link to the catalytic cysteine of M to inhibit its activity. We demonstrate that targeting the active site cysteine of M can have profound allosteric effects, distorting secondary structures to disrupt the active dimeric unit.

PubMed: 35702321
DOI: 10.1016/j.apsb.2022.06.002

Experimental method

X-RAY DIFFRACTION (2.05 Å)