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7T8R

Co-crystal structure of SARS-CoV-2 Mpro C145A with substrate peptide 7/8

Summary for 7T8R
Entry DOI10.2210/pdb7t8r/pdb
Descriptor3C-like proteinase, Nonstructural protein 7/8, 1,2-ETHANEDIOL, ... (5 entities in total)
Functional Keywordscoronavirus, covid-19, covid, protease, drug resistance, complex, hydrolase, durg discovery, main protease, mpro, substrate complex, nsp 4/5, viral protein
Biological sourceSevere acute respiratory syndrome coronavirus 2
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Total number of polymer chains2
Total formula weight35145.00
Authors
Shaqra, A.M.,Schiffer, C.A. (deposition date: 2021-12-16, release date: 2022-06-22, Last modification date: 2023-10-18)
Primary citationShaqra, A.M.,Zvornicanin, S.N.,Huang, Q.Y.J.,Lockbaum, G.J.,Knapp, M.,Tandeske, L.,Bakan, D.T.,Flynn, J.,Bolon, D.N.A.,Moquin, S.,Dovala, D.,Kurt Yilmaz, N.,Schiffer, C.A.
Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance.
Nat Commun, 13:3556-3556, 2022
Cited by
PubMed Abstract: Coronaviruses can evolve and spread rapidly to cause severe disease morbidity and mortality, as exemplified by SARS-CoV-2 variants of the COVID-19 pandemic. Although currently available vaccines remain mostly effective against SARS-CoV-2 variants, additional treatment strategies are needed. Inhibitors that target essential viral enzymes, such as proteases and polymerases, represent key classes of antivirals. However, clinical use of antiviral therapies inevitably leads to emergence of drug resistance. In this study we implemented a strategy to pre-emptively address drug resistance to protease inhibitors targeting the main protease (M) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution cocrystal structures of SARS-CoV-2 M bound to substrate peptides and six structures with cleavage products. These structures enabled us to define the substrate envelope of M, map the critical recognition elements, and identify evolutionarily vulnerable sites that may be susceptible to resistance mutations that would compromise binding of the newly developed M inhibitors. Our results suggest strategies for developing robust inhibitors against SARS-CoV-2 that will retain longer-lasting efficacy against this evolving viral pathogen.
PubMed: 35729165
DOI: 10.1038/s41467-022-31210-w
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.74 Å)
Structure validation

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