Nature CommunicationsMolecular BiologyPeer-reviewed journal article
Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro
Mikhail A. HameediiD, Erica Teixeira PratesiD, Michael R. GarviniD, Irimpan I. MathewsiD, B Kirtley AmosiD, Omar DemerdashiD, Mark Bechthold, Mamta IyeriD, Simin RahighiiD, Daniel W. KnelleriD, Andrey Y. KovalevskyiD, Stephan IrleiD, Van‐Quan VuongiD, Julie C. MitchelliD, Audrey D. Labbe, Stephanie S. GalanieiD, Soichi Wakatsuki AiD, Daniel JacobsoniD
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.
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