Structural and Functional Significance of the Amino Acid Differences Val35Thr, Ser46Ala, Asn65Ser, and Ala94Ser in 3C-like Proteinases from SARS-CoV-2 and SARS-CoV
Document Type
Article
Publication Date
2021
Keywords
(Chymo)trypsin-like Proteinases, Catalytic Tetrad, Structural Catalytic Core, Interdomain Loop, Autolysis, COVID-19, Sars-cov-2
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.ijbiomac.2021.11.043
Abstract
Three dimensional structures of (chymo)trypsin-like proteinase (3CLpro) from SARS-CoV-2 and SARS-CoV differ at 8 positions. We previously found that the Val86Leu, Lys88Arg, Phe134His, and Asn180Lys mutations in these enzymes can change the orientation of the N- and C-terminal domains of 3CLpro relative to each other, which leads to a change in catalytic activity. This conclusion was derived from the comparison of the structural catalytic core in 169 (chymo)trypsin-like proteinases with the serine/cysteine fold. Val35Thr, Ser46Ala, Asn65Ser, Ala94Ser mutations were not included in that analysis, since they are located far from the catalytic tetrad. In the present work, the structural and functional roles of these variable amino acids at positions 35, 46, 65, and 94 in the 3CLpro sequences of SARS-CoV-2 and SARS-CoV have been established using a comparison of the same set of proteinases leading to the identification of new conservative elements. Comparative analysis showed that, in addition to interdomain mobility, which could modulate catalytic activity, the 3CLpro(s) can use for functional regulation an autolytic loop and the unique Asp33-Asn95 region (the Asp33-Asn95 Zone) in the N-terminal domain. Therefore, all 4 analyzed mutation sites are associated with the unique structure-functional features of the 3CLpro from SARS-CoV-2 and SARS-CoV. Strictly speaking, the presented structural results are hypothetical, since at present there is not a single experimental work on the identification and characterization of autolysis sites in these proteases.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
International Journal of Biological Macromolecules, v. 193, issue Part B, p. 2113-2120
Scholar Commons Citation
Denesyuk, Alexander I.; Permyakov, Eugene A.; Johnson, Mark S.; Permyakov, Sergei E.; Denessiouk, Konstantin A.; and Uversky, Vladimir N., "Structural and Functional Significance of the Amino Acid Differences Val35Thr, Ser46Ala, Asn65Ser, and Ala94Ser in 3C-like Proteinases from SARS-CoV-2 and SARS-CoV" (2021). Molecular Medicine Faculty Publications. 996.
https://digitalcommons.usf.edu/mme_facpub/996
