Crystal structures of SARS-CoV-2 ADP-ribose phosphatase: from the apo form to ligand complexes

Among 15 nonstructural proteins (Nsps), the newly emerging Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) encodes a large, multidomain Nsp3. One of its units is the ADP-ribose phosphatase domain (ADRP; also known as the macrodomain, MacroD), which is believed to interfere with the host...

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Published in:IUCrJ Vol. 7; no. 5; pp. 814 - 824
Main Authors: Michalska, Karolina, Kim, Youngchang, Jedrzejczak, Robert, Maltseva, Natalia I., Stols, Lucy, Endres, Michael, Joachimiak, Andrzej
Format: Journal Article
Language:English
Published: England International Union of Crystallography 01.09.2020
Subjects:
ADP-ribose phosphatase domain
ADP-ribosylation
ADRP
BASIC BIOLOGICAL SCIENCES
Coordination compounds
Coronaviruses
COVID-19
Crystal structure
Enzymes
Health aspects
Homology
Ligands
Mac1
macrodomain
Monosaccharides
Nsp3
Phosphatase
Phosphatases
Proteins
Research Papers
Ribose
RNA
SARS-CoV-2
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Viral diseases
Water chemistry
COVID-19
SARS-CoV-2
Mac1
crystal structure
macrodomain
ADP-ribose phosphatase domain
Nsp3
ADP-ribosylation
ADRP
ISSN:2052-2525, 2052-2525
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Summary:Among 15 nonstructural proteins (Nsps), the newly emerging Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) encodes a large, multidomain Nsp3. One of its units is the ADP-ribose phosphatase domain (ADRP; also known as the macrodomain, MacroD), which is believed to interfere with the host immune response. Such a function appears to be linked to the ability of the protein to remove ADP-ribose from ADP-ribosylated proteins and RNA, yet the precise role and molecular targets of the enzyme remain unknown. Here, five high-resolution (1.07–2.01 Å) crystal structures corresponding to the apo form of the protein and its complexes with 2-( N -morpholino)ethanesulfonic acid (MES), AMP and ADP-ribose have been determined. The protein is shown to undergo conformational changes to adapt to the ligand in the manner previously observed in close homologues from other viruses. A conserved water molecule is also identified that may participate in hydrolysis. This work builds foundations for future structure-based research on ADRP, including the search for potential antiviral therapeutics.
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AC02-06CH11357
National Institutes of Health (NIH) - National Institute of Allergy and Infectious Diseases (NIAID)
USDOE Office of Science (SC), Biological and Environmental Research (BER)
These authors made equal contributions.
ISSN:2052-2525
2052-2525
DOI:10.1107/S2052252520009653