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Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro
Mikhail Ali Hameedi1,2,3,4, Erica T Prates5,4, Michael R Garvin5,4
1SLAC National Accelerator Laboratory, Stanford Synchrotron Radiation Lightsource, Structural Molecular Biology, Menlo Park, CA 94025, USA.
Biorxiv : the Preprint Server for Biology
|November 24, 2021
Summary
The SARS-CoV-2 3C-like protease cleaves human NEMO, disrupting immune responses. Structural and computational analyses reveal how this viral protease interacts with host proteins, impacting COVID-19.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- The SARS-CoV-2 3C-like protease (3CLpro) is crucial for viral replication.
- 3CLpro can also target host immune proteins, potentially dysregulating the immune response.
- NF-κB Essential Modulator (NEMO) is a key signaling protein in the human immune system.
Approach:
- Utilized in vitro assays to demonstrate 3CLpro's cleavage of NEMO.
- Determined the 2.14 Å resolution crystal structure of 3CLpro C145S bound to a NEMO peptide (NEMO226-235).
- Employed machine learning and physics-based computational methods to analyze binding interactions and predict functional implications.
Key Points:
- SARS-CoV-2 3CLpro efficiently cleaves the human immune protein NEMO.
- Structural analysis revealed specific binding subsites in 3CLpro that accommodate diverse substrates via hydrogen bonds and hydrophobic interactions.
- Computational predictions suggest that variations in key binding residues contribute to SARS-CoV-2's high infectivity.
Conclusions:
- Cleavage of NEMO by SARS-CoV-2 3CLpro is a significant mechanism affecting host immune response.
- Understanding these interactions provides insights into COVID-19 pathogenesis.
- The study highlights the dual role of 3CLpro in viral processing and host immune modulation.
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