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10.1128/JVI.01969-20

http://scihub22266oqcxt.onion/10.1128/JVI.01969-20
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33158944!7925111!33158944
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suck abstract from ncbi


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pmid33158944      J+Virol 2021 ; 95 (3): ä
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  • The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase #MMPMID33158944
  • Alhammad YMO; Kashipathy MM; Roy A; Gagne JP; McDonald P; Gao P; Nonfoux L; Battaile KP; Johnson DK; Holmstrom ED; Poirier GG; Lovell S; Fehr AR
  • J Virol 2021[Jan]; 95 (3): ä PMID33158944show ga
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-related CoVs encode 3 tandem macrodomains within nonstructural protein 3 (nsp3). The first macrodomain, Mac1, is conserved throughout CoVs and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated antiviral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Here, we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose. SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) Mac1 domains exhibit similar structural folds, and all 3 proteins bound to ADP-ribose with affinities in the low micromolar range. Importantly, using ADP-ribose-detecting binding reagents in both a gel-based assay and novel enzyme-linked immunosorbent assays (ELISAs), we demonstrated de-MARylating activity for all 3 CoV Mac1 proteins, with the SARS-CoV-2 Mac1 protein leading to a more rapid loss of substrate than the others. In addition, none of these enzymes could hydrolyze poly-ADP-ribose. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are MAR-hydrolases with similar functions, indicating that compounds targeting CoV Mac1 proteins may have broad anti-CoV activity.IMPORTANCE SARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused more than 1.2 million deaths worldwide. With no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose adducts from proteins in a dynamic posttranslational process that is increasingly being recognized as an important factor that regulates viral infection. The macrodomain is essential for CoV pathogenesis and may be a novel therapeutic target. Thus, understanding its biochemistry and enzyme activity are critical first steps for these efforts. Here, we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose and describe its ADP-ribose binding and hydrolysis activities in direct comparison to those of SARS-CoV and MERS-CoV Mac1 proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.
  • |Adenosine Diphosphate Ribose/chemistry/metabolism[MESH]
  • |Amino Acid Sequence[MESH]
  • |Coronavirus/chemistry/enzymology/metabolism[MESH]
  • |Crystallography, X-Ray[MESH]
  • |Humans[MESH]
  • |Hydrolysis[MESH]
  • |Kinetics[MESH]
  • |N-Glycosyl Hydrolases/chemistry/*metabolism[MESH]
  • |Protein Binding[MESH]
  • |Protein Domains[MESH]
  • |SARS-CoV-2/chemistry/*enzymology/metabolism[MESH]


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