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Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro
Mikhail Ali Hameedi; Erica Teixeira Prates; Michael R Garvin; Irimpan Mathews; B Kirtley Amos; Omar Demerdash; Mark Bechthold; Mamta Iyer; Simin Rahighi; Daniel W. Kneller; Andrey Kovalevsky; Stephan Irle; Van-Quan Vuong; Julie C Mitchell; Audrey Labbe; Stephanie Galanie; Soichi Wakatsuki; Daniel Jacobson.
  • Mikhail Ali Hameedi; Stanford University
  • Erica Teixeira Prates; Oak Ridge National Laboratory
  • Michael R Garvin; Oak Ridge National Laboratory
  • Irimpan Mathews; SLAC National Accelerator Laboratory
  • B Kirtley Amos; University of Kentucky
  • Omar Demerdash; Oak Ridge National Laboratory
  • Mark Bechthold; Stanford University
  • Mamta Iyer; Chapman University School of Pharmacy
  • Simin Rahighi; Chapman University School of Pharmacy
  • Daniel W. Kneller; Oak Ridge National Laboratory
  • Andrey Kovalevsky; Oak Ridge National Laboratory
  • Stephan Irle; Oak Ridge National Laboratory
  • Van-Quan Vuong; University of Tennessee Knoxville
  • Julie C Mitchell; Oak Ridge National Laboratory
  • Audrey Labbe; Oak Ridge National Laboratory
  • Stephanie Galanie; Merck & Co., Inc.
  • Soichi Wakatsuki; Stanford University
  • Daniel Jacobson; Oak Ridge National Laboratory
Preprint Dans Anglais | bioRxiv | ID: ppbiorxiv-468228
ABSTRACT
In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like (3CLpro) protease can cleave human immune signaling proteins, like NF-{kappa}B Essential Modulator (NEMO) and deregulate the host immune response. Here, in vitro assays show that SARS-CoV-2 3CLpro cleaves NEMO with fine-tuned efficiency. Analysis of the 2.14 [A] resolution crystal structure of 3CLpro C145S bound to NEMO226-235 reveals subsites that tolerate a range of viral and host substrates through main chain hydrogen bonds while also enforcing specificity using side chain hydrogen bonds and hydrophobic contacts. Machine learning- and physics-based computational methods predict that variation in key binding residues of 3CLpro- NEMO helps explain the high fitness of SARS-CoV-2 in humans. We posit that cleavage of NEMO is an important piece of information to be accounted for in the pathology of COVID-19.
Texte intégral: Disponible Collection: Preprints Base de données: bioRxiv langue: Anglais Année: 2021 Type de document: Preprint

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Texte intégral: Disponible Collection: Preprints Base de données: bioRxiv langue: Anglais Année: 2021 Type de document: Preprint