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Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro

by Wakatsuki, Soichi , Irle, Stephan , Demerdash, Omar , Kovalevsky, Andrey , Galanie, Stephanie , T. Prates, Erica , Amos, B. Kirtley , Jacobson, Daniel , Garvin, Michael R. , Mathews, Irimpan I. , Kneller, Daniel W. , Vuong, Van-Quan , Bechthold, Mark , Rahighi, Simin , Mitchell, Julie C. , Iyer, Mamta , Hameedi, Mikhail A. , Labbe, Audrey

in 631/535/1266 / 692/420/254 / Antiviral Agents - chemistry / Bonding / Chains / Cleavage / Computer applications / COVID-19 / Crystal structure / Crystallography / Cysteine Endopeptidases - metabolism / Deregulation / Fitness / Humanities and Social Sciences / Humans / Hydrogen bonding / Hydrogen bonds / Hydrophobicity / Immune response / Immune system / Machine learning / multidisciplinary / NF-κB protein / Peptide Hydrolases / Proteins / SARS-CoV-2 / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Structural analysis / Structure-function relationships / Substrates

2022

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2022

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2022

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Journal Article

Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro

Wakatsuki, Soichi,

Irle, Stephan,

Demerdash, Omar,

Kovalevsky, Andrey,

Galanie, Stephanie,

T. Prates, Erica,

Amos, B. Kirtley,

Jacobson, Daniel,

Garvin, Michael R.,

Mathews, Irimpan I.,

Kneller, Daniel W.,

Vuong, Van-Quan,

Bechthold, Mark,

Rahighi, Simin,

Mitchell, Julie C.,

Iyer, Mamta,

Hameedi, Mikhail A.,

Labbe, Audrey

2022

Overview

In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like protease (3CLpro) can cleave human immune signaling proteins, like NF-κB 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 2.50 Å resolution crystal structure of 3CLpro C145S bound to NEMO 226–234 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. The authors report crystallographic and computational studies that detail how SARS-CoV-2 3CLpro cleaves the host NF-κB Essential Modulator in addition to its canonical viral substrates. The association with the high fitness of SARS-CoV-2 in humans is discussed.

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Publisher

Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio

Subject

631/535/1266

/ 692/420/254

/ Antiviral Agents - chemistry

/ Bonding

/ Chains

/ Cleavage

/ Computer applications