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The SARS-CoV-2 conserved macrodomain is a highly efficient ADP-ribosylhydrolase enzyme.
bioRxiv. 2020 May 12B

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like-CoVs encode 3 tandem macrodomains within non-structural protein 3 (nsp3). The first of these macrodomains, termed Mac1, is conserved throughout CoVs, binds to mono- and poly-ADP-ribose, and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating this domain as a prominent virulence factor and potential therapeutic target. Mac1 likely counters host-mediated antiviral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose refined at 2.2 Å resolution. SARS-CoV-2, SARS-CoV and MERS-CoV Mac1 exhibit similar structural folds and ADP-ribose binding modes as shown by structural comparison. All three CoV Mac1 proteins bound to ADP-ribose with low μM affinities. They also demonstrated highly efficient de-MARylating activity, which was greater than that of the human Mdo2 macrodomain. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are highly efficient ADP-ribosylhydrolases with strikingly similar activity, indicating that compounds targeting CoV Mac1 proteins may have broad antiviral activity against CoVs.

IMPORTANCE

SARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused nearly 300K deaths worldwide. With, no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode for a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose, a post-translation modification, from proteins. This protein domain 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 SARS-CoV and MERS-CoV Mac1 proteins, and a human macrodomain. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.

Authors

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Pub Type(s)

Preprint

Language

eng

PubMed ID

32511412

Citation

Alhammad, Yousef M O., et al. "The SARS-CoV-2 Conserved Macrodomain Is a Highly Efficient ADP-ribosylhydrolase Enzyme." BioRxiv : the Preprint Server for Biology, 2020.
Alhammad YMO, Kashipathy MM, Roy A, et al. The SARS-CoV-2 conserved macrodomain is a highly efficient ADP-ribosylhydrolase enzyme. bioRxiv : the preprint server for biology. 2020.
Alhammad, Y. M. O., Kashipathy, M. M., Roy, A., Johnson, D. K., McDonald, P., Battaile, K. P., Gao, P., Lovell, S., & Fehr, A. R. (2020). The SARS-CoV-2 conserved macrodomain is a highly efficient ADP-ribosylhydrolase enzyme. BioRxiv : the Preprint Server for Biology. https://doi.org/10.1101/2020.05.11.089375
Alhammad YMO, et al. The SARS-CoV-2 Conserved Macrodomain Is a Highly Efficient ADP-ribosylhydrolase Enzyme. bioRxiv : the preprint server for biology. 2020 May 12; PubMed PMID: 32511412.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The SARS-CoV-2 conserved macrodomain is a highly efficient ADP-ribosylhydrolase enzyme. AU - Alhammad,Yousef M O, AU - Kashipathy,Maithri M, AU - Roy,Anuradha, AU - Johnson,David K, AU - McDonald,Peter, AU - Battaile,Kevin P, AU - Gao,Philip, AU - Lovell,Scott, AU - Fehr,Anthony R, Y1 - 2020/05/12/ PY - 2020/6/9/entrez PY - 2020/6/9/pubmed PY - 2020/6/9/medline JF - bioRxiv : the preprint server for biology N2 - : Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like-CoVs encode 3 tandem macrodomains within non-structural protein 3 (nsp3). The first of these macrodomains, termed Mac1, is conserved throughout CoVs, binds to mono- and poly-ADP-ribose, and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating this domain as a prominent virulence factor and potential therapeutic target. Mac1 likely counters host-mediated antiviral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose refined at 2.2 Å resolution. SARS-CoV-2, SARS-CoV and MERS-CoV Mac1 exhibit similar structural folds and ADP-ribose binding modes as shown by structural comparison. All three CoV Mac1 proteins bound to ADP-ribose with low μM affinities. They also demonstrated highly efficient de-MARylating activity, which was greater than that of the human Mdo2 macrodomain. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are highly efficient ADP-ribosylhydrolases with strikingly similar activity, indicating that compounds targeting CoV Mac1 proteins may have broad antiviral activity against CoVs. IMPORTANCE: SARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused nearly 300K deaths worldwide. With, no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode for a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose, a post-translation modification, from proteins. This protein domain 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 SARS-CoV and MERS-CoV Mac1 proteins, and a human macrodomain. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain. UR - https://www.unboundmedicine.com/medline/citation/32511412/The_SARS_CoV_2_conserved_macrodomain_is_a_highly_efficient_ADP_ribosylhydrolase_enzyme_ L2 - https://doi.org/10.1101/2020.05.11.089375 DB - PRIME DP - Unbound Medicine ER -
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