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Structural stability of the SARS-CoV-2 main protease: Can metal ions affect function?

Kozak, John J. and Gray, Harry B. and Garza-López, Roberto A. (2020) Structural stability of the SARS-CoV-2 main protease: Can metal ions affect function? Journal of Inorganic Biochemistry, 211 . Art. No. 111179. ISSN 0162-0134. PMCID PMC7365078. doi:10.1016/j.jinorgbio.2020.111179.

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We have investigated the structural stability of the SARS (Severe acute respiratory syndrome)-CoV-2 main protease monomer (Mpro). We quantified the spatial and angular changes in the structure using two independent analyses, one based on a spatial metrics (δ, ratio), the second on angular metrics. The order of unfolding of the 10 helices in Mpro is characterized by beta vs alpha plots similar to those of cytochromes and globins. The longest turning region is anomalous in the earliest stage of unfolding. In an investigation of excluded-volume effects, we found that the maximum spread in average molecular-volume values for Mpro, cytochrome c-b₅₆₂, cytochrome c’, myoglobin, and cytoglobin is ~10 ų. This apparent universality is a consequence of the dominant contributions from six residues: ALA, ASP, GLU, LEU, LYS and VAL. Of the seven Mpro histidines, residues 41, 163, 164, and 246 are in stable H-bonded regions; metal ion binding to one or more of these residues could break up the H-bond network, thereby affecting protease function. Our analysis also indicated that metal binding to cysteine residues 44 and 145 could disable the enzyme.

Item Type:Article
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Gray, Harry B.0000-0002-7937-7876
Additional Information:© 2020 Elsevier Inc. Received 26 May 2020, Revised 8 July 2020, Accepted 10 July 2020, Available online 16 July 2020. Work at Caltech was supported by the NIH (DK019038) and the Arnold and Mabel Beckman Foundation. Support at Pomona College was provided by the Howard Hughes Medical Institute Research Program and a Sontag Research Fellowship Award. Molecular graphics and analyses performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Funding AgencyGrant Number
Arnold and Mabel Beckman FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Sontag FoundationUNSPECIFIED
University of California, San FranciscoUNSPECIFIED
PubMed Central ID:PMC7365078
Record Number:CaltechAUTHORS:20200716-094538897
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Official Citation:John J. Kozak, Harry B. Gray, Roberto A. Garza-López, Structural stability of the SARS-CoV-2 main protease: Can metal ions affect function?, Journal of Inorganic Biochemistry, Volume 211, 2020, 111179, ISSN 0162-0134, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104400
Deposited By: Tony Diaz
Deposited On:16 Jul 2020 17:45
Last Modified:16 Nov 2021 18:31

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