7MB5
SARS-CoV-2 Main Protease (Mpro) C145A in Complex with Cleavage Site Nsp5/6 (P6-P1)
Summary for 7MB5
| Entry DOI | 10.2210/pdb7mb5/pdb |
| Descriptor | 3C-like proteinase, SER-GLY-VAL-THR-PHE-GLN (3 entities in total) |
| Functional Keywords | sars-cov-2, covid-19, covid19 protease, protease inhibitor, complex, hydrolase inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2) More |
| Total number of polymer chains | 4 |
| Total formula weight | 68862.32 |
| Authors | Lockbaum, G.J.,Schiffer, C.A. (deposition date: 2021-03-31, release date: 2022-06-22, Last modification date: 2023-10-18) |
| Primary citation | Shaqra, 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: 35729165DOI: 10.1038/s41467-022-31210-w PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
Download full validation report
