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HGNC Genes

SARS-CoV-2 proteins

NSP3 (1)


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    The SARS-CoV-2 conserved macrodomain is a highly efficient ADP-ribosylhydrolase enzyme

    Authors: Yousef M.O. Alhammad; Maithri M. Kashipathy; Anuradha Roy; Jean-Philippe Gagne; Louis Nonfoux; Peter McDonald; Philip Gao; Kevin P. Battaile; David K. Johnson; Guy G Poirier; Scott W. Lovell; Anthony R. Fehr

    doi:10.1101/2020.05.11.089375 Date: 2020-05-12 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like-CoVs encode 3 tandem macrodomains within non-structural protein 3 PROTEIN (nsp3). The first macrodomain, Mac1 HGNC, is conserved throughout CoVs, binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 HGNC likely counters host-mediated anti-viral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Mac1 HGNC is essential for pathogenesis in multiple animal models of CoV infection MESHD, implicating it as a virulence factor and potential therapeutic target. Here we report the crystal structure of SARS-CoV-2 Mac1 HGNC in complex with ADP-ribose. SARS-CoV-2, SARS-CoV MESHD and MERS-CoV Mac1 HGNC exhibit similar structural folds and all 3 proteins bound to ADP-ribose with low M affinities. In contrast, we found that only the MERS-CoV Mac1 HGNC protein bound to poly-ADP-ribose (PAR), and none of these enzymes could hydrolyze PAR. Importantly, using ADP-ribose detecting antibodies and both gel-based assay and novel ELISA assays, we demonstrated highly efficient de-MARylating activity for all 3 CoV Mac1 HGNC proteins. We conclude that the SARS-CoV-2 and other CoV Mac1 HGNC proteins are highly efficient MAR-hydrolases with strikingly similar activity, indicating that compounds targeting CoV Mac1 HGNC proteins may have broad anti-CoV activity. IMPORTANCESARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 MESHD that has caused nearly 350 thousand deaths worldwide. With, no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode for a highly conserved macrodomain ( Mac1 HGNC) that binds to and removes ADP-ribose adducts from proteins in a dynamic post-translational process increasingly 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 HGNC in complex with ADP-ribose, and describe its ADP-ribose binding and hydrolysis activities in direct comparison to SARS-CoV and MERS-CoV Mac1 HGNC proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.

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MeSH Disease
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