7tx3 Citations

The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and x-ray diffraction at room temperature.

Abstract

The nonstructural protein 3 (NSP3) macrodomain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Mac1) removes adenosine diphosphate (ADP) ribosylation posttranslational modifications, playing a key role in the immune evasion capabilities of the virus responsible for the coronavirus disease 2019 pandemic. Here, we determined neutron and x-ray crystal structures of the SARS-CoV-2 NSP3 macrodomain using multiple crystal forms, temperatures, and pHs, across the apo and ADP-ribose-bound states. We characterize extensive solvation in the Mac1 active site and visualize how water networks reorganize upon binding of ADP-ribose and non-native ligands, inspiring strategies for displacing waters to increase the potency of Mac1 inhibitors. Determining the precise orientations of active site water molecules and the protonation states of key catalytic site residues by neutron crystallography suggests a catalytic mechanism for coronavirus macrodomains distinct from the substrate-assisted mechanism proposed for human MacroD2. These data provoke a reevaluation of macrodomain catalytic mechanisms and will guide the optimization of Mac1 inhibitors.

Articles - 7tx3 mentioned but not cited (3)

  1. The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and x-ray diffraction at room temperature. Correy GJ, Kneller DW, Phillips G, Pant S, Russi S, Cohen AE, Meigs G, Holton JM, Gahbauer S, Thompson MC, Ashworth A, Coates L, Kovalevsky A, Meilleur F, Fraser JS. Sci Adv 8 eabo5083 (2022)
  2. Neutron crystallographic refinement with REFMAC5 from the CCP4 suite. Catapano L, Long F, Yamashita K, Nicholls RA, Steiner RA, Murshudov GN. Acta Crystallogr D Struct Biol 79 1056-1070 (2023)
  3. research-article The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and X-ray diffraction at room temperature. Correy GJ, Kneller DW, Phillips G, Pant S, Russi S, Cohen AE, Meigs G, Holton JM, Gahbauer S, Thompson MC, Ashworth A, Coates L, Kovalevsky A, Meilleur F, Fraser JS. bioRxiv 2022.02.07.479477 (2022)


Reviews citing this publication (4)

  1. Improved understanding of biorisk for research involving microbial modification using annotated sequences of concern. Godbold GD, Hewitt FC, Kappell AD, Scholz MB, Agar SL, Treangen TJ, Ternus KL, Sandbrink JB, Koblentz GD. Front Bioeng Biotechnol 11 1124100 (2023)
  2. ADP-ribosylation from molecular mechanisms to therapeutic implications. Suskiewicz MJ, Prokhorova E, Rack JGM, Ahel I. Cell 186 4475-4495 (2023)
  3. An Update on the Current State of SARS-CoV-2 Mac1 Inhibitors. O'Connor JJ, Ferraris D, Fehr AR. Pathogens 12 1221 (2023)
  4. PARPs and ADP-Ribosylation in Chronic Inflammation: A Focus on Macrophages. Santinelli-Pestana DV, Aikawa E, Singh SA, Aikawa M. Pathogens 12 964 (2023)

Articles citing this publication (9)