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Basic Characteristics of Mutations
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Mutation Site
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G11S |
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Mutation Site Sentence
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A naturally occurring G11S mutation in the 3C-like protease from the SARS-CoV-2 virus dramatically weakens the dimer interface. |
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Mutation Level
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Amino acid level |
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Mutation Type
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Nonsynonymous substitution |
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Gene/Protein/Region
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3CLpro |
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Standardized Encoding Gene
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ORF1a
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Genotype/Subtype
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- |
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Viral Reference
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WIV04 Official GISAID
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Functional Impact and Mechanisms
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Disease
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COVID-19
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Immune
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- |
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Target Gene
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-
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Clinical and Epidemiological Correlations
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Clinical Information
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- |
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Treatment
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- |
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Location
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- |
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Literature Information
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PMID
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38058248
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Title
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A naturally occurring G11S mutation in the 3C-like protease from the SARS-CoV-2 virus dramatically weakens the dimer interface
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Author
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Wang G,Venegas FA,Rueda AM,Weerasinghe NW,Uggowitzer KA,Thibodeaux CJ,Moitessier N,Mittermaier AK
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Journal
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Protein science : a publication of the Protein Society
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Journal Info
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2024 Jan;33(1):e4857
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Abstract
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The 3C-like protease (3CL(pro) ) is crucial to the replication of SARS-CoV-2, the causative agent of COVID-19, and is the target of several successful drugs including Paxlovid and Xocova. Nevertheless, the emergence of viral resistance underlines the need for alternative drug strategies. 3CL(pro) only functions as a homodimer, making the protein-protein interface an attractive drug target. Dimerization is partly mediated by a conserved glycine at position 11. However, some naturally occurring SARS-CoV-2 sequences contain a serine at this position, potentially disrupting the dimer. We have used concentration-dependent activity assays and mass spectrometry to show that indeed the G11S mutation reduces the stability of the dimer by 600-fold. This helps to set a quantitative benchmark for the minimum potency required of any future protein-protein interaction inhibitors targeting 3CL(pro) and raises interesting questions regarding how coronaviruses bearing such weakly dimerizing 3CL(pro) enzymes are capable of replication.
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Sequence Data
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-
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