7TB2

Co-crystal structure of SARS-CoV-2 Mpro C145A with substrate peptide 12/13

7TB2 の概要

• エントリーDOI: 10.2210/pdb7tb2/pdb
• 分子名称: 3C-like proteinase, Nonstructural protein 12/13 (3 entities in total)
• 機能のキーワード: coronavirus, covid-19, covid, protease, drug resistance, complex, hydrolase, durg discovery, main protease, mpro, substrate complex, nsp 12/13, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34658.49

構造登録者

Shaqra, A.M.,Schiffer, C.A. (登録日: 2021-12-21, 公開日: 2022-06-22, 最終更新日: 2023-10-18)

主引用文献

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

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

実験手法

X-RAY DIFFRACTION (1.8 Å)