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Structural stability of the SARS-CoV-2 main protease: Can metal ions affect function?
John J Kozak1, Harry B Gray2, Roberto A Garza-López3
1Department of Chemistry, DePaul University, Chicago, IL 60604-6116, United States of America.
Journal of Inorganic Biochemistry
|August 1, 2020
Summary
This study analyzed the structural stability of SARS-CoV-2 main protease (Mpro), revealing how its helices unfold and identifying key residues sensitive to metal ion binding, which could impact protease function.
Area of Science:
- Biochemistry
- Structural Biology
- Virology
Background:
- The SARS-CoV-2 main protease (Mpro) is a critical enzyme for viral replication.
- Understanding Mpro's structural dynamics is essential for developing antiviral strategies.
Purpose of the Study:
- To investigate the structural stability and unfolding pathways of the SARS-CoV-2 Mpro monomer.
- To identify specific residues and regions susceptible to structural changes and functional impairment.
Main Methods:
- Utilized spatial and angular metrics to quantify structural changes during Mpro unfolding.
- Analyzed helix unfolding order using beta vs alpha plots, comparing Mpro to other globins.
- Investigated excluded-volume effects and contributions of specific amino acid residues to molecular volume.
Main Results:
- Characterized the unfolding order of Mpro's 10 helices, noting an anomalous turning region.
- Observed a universal trend in excluded-volume effects across Mpro and related proteins, driven by six key residues.
- Identified specific histidine and cysteine residues in Mpro that are critical for structural integrity and function, and susceptible to metal ion binding.
Conclusions:
- The structural stability of SARS-CoV-2 Mpro is characterized by a defined helix unfolding pathway.
- Specific residues, particularly histidines and cysteines, play crucial roles in Mpro's structural integrity and enzymatic activity.
- Metal ion binding to these identified residues could potentially inhibit Mpro function, offering a target for antiviral drug design.
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