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Article ; Online: The Viral Macrodomain Counters Host Antiviral ADP-Ribosylation.

Alhammad, Yousef M O / Fehr, Anthony R

2020 Volume 12, Issue 4

Abstract: Macrodomains, enzymes that remove ADP-ribose from proteins, are encoded by several families of RNA viruses and have recently been shown to counter innate immune responses to virus infection. ADP-ribose is covalently attached to target proteins by poly- ... ...

Abstract	Macrodomains, enzymes that remove ADP-ribose from proteins, are encoded by several families of RNA viruses and have recently been shown to counter innate immune responses to virus infection. ADP-ribose is covalently attached to target proteins by poly-ADP-ribose polymerases (PARPs), using nicotinamide adenine dinucleotide (NAD+) as a substrate. This modification can have a wide variety of effects on proteins including alteration of enzyme activity, protein-protein interactions, and protein stability. Several PARPs are induced by interferon (IFN) and are known to have antiviral properties, implicating ADP-ribosylation in the host defense response and suggesting that viral macrodomains may counter this response. Recent studies have demonstrated that viral macrodomains do counter the innate immune response by interfering with PARP-mediated antiviral defenses, stress granule formation, and pro-inflammatory cytokine production. Here, we will describe the known functions of the viral macrodomains and review recent literature demonstrating their roles in countering PARP-mediated antiviral responses.
MeSH term(s)	ADP-Ribosylation/immunology ; Adenosine Diphosphate Ribose/metabolism ; Cytoplasmic Granules/immunology ; Cytoplasmic Granules/virology ; Humans ; Interferons/immunology ; Mutation ; Poly(ADP-ribose) Polymerases/immunology ; Protein Domains ; RNA Virus Infections/immunology ; RNA Virus Infections/metabolism ; RNA Virus Infections/virology ; RNA Viruses/classification ; RNA Viruses/genetics ; RNA Viruses/immunology ; RNA Viruses/metabolism ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/immunology ; Viral Nonstructural Proteins/metabolism ; Virus Replication
Chemical Substances	Viral Nonstructural Proteins ; Adenosine Diphosphate Ribose (20762-30-5) ; Interferons (9008-11-1) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30)
Keywords	covid19
Language	English
Publishing date	2020-03-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v12040384
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The Viral Macrodomain Counters Host Antiviral ADP-Ribosylation

Alhammad, Yousef M. O. / Fehr, Anthony R.

Viruses

Abstract: Macrodomains, enzymes that remove ADP-ribose from proteins, are encoded by several families of RNA viruses and have recently been shown to counter innate immune responses to virus infection ADP-ribose is covalently attached to target proteins by poly-ADP- ...

Abstract	Macrodomains, enzymes that remove ADP-ribose from proteins, are encoded by several families of RNA viruses and have recently been shown to counter innate immune responses to virus infection ADP-ribose is covalently attached to target proteins by poly-ADP-ribose polymerases (PARPs), using nicotinamide adenine dinucleotide (NAD+) as a substrate This modification can have a wide variety of effects on proteins including alteration of enzyme activity, protein–protein interactions, and protein stability Several PARPs are induced by interferon (IFN) and are known to have antiviral properties, implicating ADP-ribosylation in the host defense response and suggesting that viral macrodomains may counter this response Recent studies have demonstrated that viral macrodomains do counter the innate immune response by interfering with PARP-mediated antiviral defenses, stress granule formation, and pro-inflammatory cytokine production Here, we will describe the known functions of the viral macrodomains and review recent literature demonstrating their roles in countering PARP-mediated antiviral responses
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #820253
Database	COVID19

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Article ; Online: Mutation of highly conserved residues in loop 2 of the coronavirus macrodomain demonstrates that enhanced ADP-ribose binding is detrimental to infection

Kerr, Catherine M. / Pfannenstiel, Jessica J. / Alhammad, Yousef M. / Roy, Anuradha / O’Connor, Joseph J. / Ghimire, Roshan / Khattabi, Reem / Shrestha, Rakshya / McDonald, Peter R. / Gao, Philip / Johnson, David K. / More, Sunil / Channappanavar, Rudragouda / Fehr, Anthony R.

bioRxiv

Abstract: All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown that Mac1 is important ... ...

Abstract	All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown that Mac1 is important for virus replication and pathogenesis. Within Mac1, there are several regions that are highly conserved across CoVs, including the GIF (glycine-isoleucine-phenylalanine) motif. To determine how the biochemical activities of these residues impact CoV replication, the isoleucine and the phenylalanine residues were mutated to alanine (I-A/F-A) in both recombinant Mac1 proteins and recombinant CoVs, including murine hepatitis virus (MHV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The F-A mutant proteins had ADP-ribose binding and/or hydrolysis defects that led to attenuated replication and pathogenesis in cell culture and mice. In contrast, the I-A mutations had normal enzyme activity and enhanced ADP-ribose binding. Despite increased ADP-ribose binding, I-A mutant MERS-CoV and SARS-CoV-2 were highly attenuated in both cell culture and mice, indicating that this isoleucine residue acts as a gate that controls ADP-ribose binding for efficient virus replication. These results highlight the function of this highly conserved residue and provide unique insight into how macrodomains control ADP-ribose binding and hydrolysis to promote viral replication and pathogenesis.
Keywords	covid19
Language	English
Publishing date	2024-01-04
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.01.03.574082
Database	COVID19

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Article: Full-Length Genome of the Equine Influenza A Virus Subtype H3N8 from 2019 Outbreak in Saudi Arabia.

Alaql, Fanan A / Alhafufi, Ali N / Kasem, Samy / Alhammad, Yousef M O / Albaqshi, Hassan / Alyousaf, Ameen / Alsubaie, Faisal M / Alghamdi, Ahmed N / Abdel-Moneim, Ahmed S / Alharbi, Sulaiman A

Animals : an open access journal from MDPI

2022 Volume 12, Issue 19

Abstract: Equine influenza is a major cause of respiratory infections in horses and can spread rapidly despite the availability of commercial vaccines. This study aimed to screen the incidence of equine influenza virus (EIV) and molecularly characterize the ... ...

Abstract	Equine influenza is a major cause of respiratory infections in horses and can spread rapidly despite the availability of commercial vaccines. This study aimed to screen the incidence of equine influenza virus (EIV) and molecularly characterize the haemagglutinin and neuraminidase from positive EIV field samples collected from Saudi Arabia. Six-hundred twenty-one horses from 57 horse barns were screened for the presence of the clinical signs, suggestive for equine influenza, from different parts of Saudi Arabia. Nasopharyngeal swabs were collected from each horse showing respiratory distress. Samples from the same horse barn were pooled together and screened for the presence of the influenza A virus using quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR). Selective positive samples were subjected to full-length genome sequencing using MiSeq Illumina. Out of the total 57 pools, 39 were found positive to EIV using qRT-PCR. Full-length gene sequences were compared with representative EIV strains selected from the GenBank database. Phylogenetic analysis of the HA and NA genes revealed that the identified virus strains belong to H3N8 clade 1 of the Florida sublineage and were very similar to viruses identified in USA in 2019, with no current evidence for reassortment. This is one of the first reports providing detailed description and characterization of EIVs in Saudi Arabia. Detailed surveillance and genetic information sharing could allow genetic evolution of equine influenza viruses to be monitored more effectively on a global basis and aid in refinement of vaccine strain selection for EIV.
Language	English
Publishing date	2022-10-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606558-7
ISSN	2076-2615
ISSN	2076-2615
DOI	10.3390/ani12192720
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Article ; Online: The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase.

Alhammad, Yousef M O / Kashipathy, Maithri M / Roy, Anuradha / Gagné, Jean-Philippe / McDonald, Peter / Gao, Philip / Nonfoux, Louis / Battaile, Kevin P / Johnson, David K / Holmstrom, Erik D / Poirier, Guy G / Lovell, Scott / Fehr, Anthony R

Journal of virology

2021 Volume 95, Issue 3

Abstract: 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- ... ...

Abstract	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.
MeSH term(s)	Adenosine Diphosphate Ribose/chemistry ; Adenosine Diphosphate Ribose/metabolism ; Amino Acid Sequence ; Coronavirus/chemistry ; Coronavirus/enzymology ; Coronavirus/metabolism ; Crystallography, X-Ray ; Humans ; Hydrolysis ; Kinetics ; N-Glycosyl Hydrolases/chemistry ; N-Glycosyl Hydrolases/metabolism ; Protein Binding ; Protein Domains ; SARS-CoV-2/chemistry ; SARS-CoV-2/enzymology ; SARS-CoV-2/metabolism ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Viral Nonstructural Proteins ; Adenosine Diphosphate Ribose (20762-30-5) ; N-Glycosyl Hydrolases (EC 3.2.2.-) ; ADP-ribosylarginine hydrolase (EC 3.2.2.19)
Keywords	covid19
Language	English
Publishing date	2021-01-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01969-20
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Article: Mutation of highly conserved residues in loop 2 of the coronavirus macrodomain demonstrates that enhanced ADP-ribose binding is detrimental to infection.

Kerr, Catherine M / Pfannenstiel, Jessica J / Alhammad, Yousef M / Roy, Anuradha / O'Connor, Joseph J / Ghimire, Roshan / Khattabi, Reem / Shrestha, Rakshya / McDonald, Peter R / Gao, Philip / Johnson, David K / More, Sunil / Channappanavar, Rudragouda / Fehr, Anthony R

bioRxiv : the preprint server for biology

2024

Abstract	All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown that Mac1 is important for virus replication and pathogenesis. Within Mac1, there are several regions that are highly conserved across CoVs, including the GIF (glycine-isoleucine-phenylalanine) motif. To determine how the biochemical activities of these residues impact CoV replication, the isoleucine and the phenylalanine residues were mutated to alanine (I-A/F-A) in both recombinant Mac1 proteins and recombinant CoVs, including murine hepatitis virus (MHV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The F-A mutant proteins had ADP-ribose binding and/or hydrolysis defects that led to attenuated replication and pathogenesis in cell culture and mice. In contrast, the I-A mutations had normal enzyme activity and enhanced ADP-ribose binding. Despite increased ADP-ribose binding, I-A mutant MERS-CoV and SARS-CoV-2 were highly attenuated in both cell culture and mice, indicating that this isoleucine residue acts as a gate that controls ADP-ribose binding for efficient virus replication. These results highlight the function of this highly conserved residue and provide unique insight into how macrodomains control ADP-ribose binding and hydrolysis to promote viral replication and pathogenesis.
Language	English
Publishing date	2024-01-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.03.574082
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: High-Throughput Activity Assay for Screening Inhibitors of the SARS-CoV-2 Mac1 Macrodomain.

Dasovich, Morgan / Zhuo, Junlin / Goodman, Jack A / Thomas, Ajit / McPherson, Robert Lyle / Jayabalan, Aravinth Kumar / Busa, Veronica F / Cheng, Shang-Jung / Murphy, Brennan A / Redinger, Karli R / Alhammad, Yousef M O / Fehr, Anthony R / Tsukamoto, Takashi / Slusher, Barbara S / Bosch, Jürgen / Wei, Huijun / Leung, Anthony K L

ACS chemical biology

2021 Volume 17, Issue 1, Page(s) 17–23

Abstract: Macrodomains are a class of conserved ADP-ribosylhydrolases expressed by viruses of pandemic concern, including coronaviruses and alphaviruses. Viral macrodomains are critical for replication and virus-induced pathogenesis; therefore, these enzymes are a ...

Abstract	Macrodomains are a class of conserved ADP-ribosylhydrolases expressed by viruses of pandemic concern, including coronaviruses and alphaviruses. Viral macrodomains are critical for replication and virus-induced pathogenesis; therefore, these enzymes are a promising target for antiviral therapy. However, no potent or selective viral macrodomain inhibitors currently exist, in part due to the lack of a high-throughput assay for this class of enzymes. Here we developed a high-throughput ADP-ribosylhydrolase assay using the SARS-CoV-2 macrodomain Mac1. We performed a pilot screen that identified dasatinib and dihydralazine as ADP-ribosylhydrolase inhibitors. Importantly, dasatinib inhibits SARS-CoV-2 and MERS-CoV Mac1 but not the closest human homologue, MacroD2. Our study demonstrates the feasibility of identifying selective inhibitors based on ADP-ribosylhydrolase activity, paving the way for the screening of large compound libraries to identify improved macrodomain inhibitors and to explore their potential as antiviral therapies for SARS-CoV-2 and future viral threats.
MeSH term(s)	Antiviral Agents/pharmacology ; Dasatinib/pharmacology ; High-Throughput Screening Assays/methods ; N-Glycosyl Hydrolases/antagonists & inhibitors ; Protein Domains ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology
Chemical Substances	Antiviral Agents ; N-Glycosyl Hydrolases (EC 3.2.2.-) ; ADP-ribosylarginine hydrolase (EC 3.2.2.19) ; Dasatinib (RBZ1571X5H)
Language	English
Publishing date	2021-12-14
Publishing country	United States
Document type	Letter
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.1c00721
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity.

Heer, Collin D / Sanderson, Daniel J / Voth, Lynden S / Alhammad, Yousef M O / Schmidt, Mark S / Trammell, Samuel A J / Perlman, Stanley / Cohen, Michael S / Fehr, Anthony R / Brenner, Charles

bioRxiv : the preprint server for biology

2020

Abstract: Poly-ADP-ribose polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using nicotinamide adenine dinucleotide (NAD) as the source of ADPR. While the well-known poly-ADP-ribosylating ( ... ...

Abstract	Poly-ADP-ribose polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using nicotinamide adenine dinucleotide (NAD) as the source of ADPR. While the well-known poly-ADP-ribosylating (PARylating) PARPs primarily function in the DNA damage response, many non-canonical mono-ADP-ribosylating (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust upregulation of several PARPs following infection with Murine Hepatitis Virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly upregulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while downregulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD
Keywords	covid19
Language	English
Publishing date	2020-10-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.04.17.047480
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Article ; Online: Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity.

Heer, Collin D / Sanderson, Daniel J / Voth, Lynden S / Alhammad, Yousef M O / Schmidt, Mark S / Trammell, Samuel A J / Perlman, Stanley / Cohen, Michael S / Fehr, Anthony R / Brenner, Charles

The Journal of biological chemistry

2020 Volume 295, Issue 52, Page(s) 17986–17996

Abstract: Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily ... ...

Abstract	Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD
MeSH term(s)	A549 Cells ; ADP-Ribosylation ; Adenosine Diphosphate Ribose/metabolism ; Adult ; Animals ; COVID-19/immunology ; COVID-19/metabolism ; Cell Line, Tumor ; Female ; Ferrets ; Humans ; Immunity, Innate ; Male ; Metabolome ; Mice ; Mice, Inbred C57BL ; NAD/immunology ; NAD/metabolism ; Niacinamide/analogs & derivatives ; Niacinamide/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerases/blood ; Poly(ADP-ribose) Polymerases/immunology ; Pyridinium Compounds ; SARS-CoV-2/immunology ; SARS-CoV-2/metabolism
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Pyridinium Compounds ; nicotinamide-beta-riboside (0I8H2M0L7N) ; NAD (0U46U6E8UK) ; Adenosine Diphosphate Ribose (20762-30-5) ; Niacinamide (25X51I8RD4) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30)
Keywords	covid19
Language	English
Publishing date	2020-10-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA120.015138
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Article: The SARS-CoV-2 conserved macrodomain is a mono-ADP-ribosylhydrolase.

bioRxiv : the preprint server for biology

2020

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 macrodomain, Mac1, is conserved throughout CoVs, and binds to and hydrolyzes mono-ADP- ... ...

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 macrodomain, Mac1, is conserved throughout CoVs, and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated anti-viral 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 MERS-CoV Mac1 exhibit similar structural folds and all 3 proteins bound to ADP-ribose with low μM affinities. Importantly, using ADP-ribose detecting binding reagents in both a gel-based assay and novel ELISA assays, 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 compared to 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 greater than 900 thousand 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 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 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. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.
Keywords	covid19
Language	English
Publishing date	2020-10-28
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.05.11.089375
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