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

<div class='caption-title'>The NSP3 macrodomain (Mac1) reverses mono-ADP ribosylation.</div>
<div class='caption-title'>Crystal structures of Mac1 determined using neutron diffraction.</div>
<div class='caption-title'>Protonation states of Mac1 residues assigned by neutron diffraction.</div>
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
OpenAccess logo Sci Adv 8 eabo5083 (2022)
Related entries: 7twf, 7twg, 7twh, 7twi, 7twj, 7twn, 7two, 7twp, 7twq, 7twr, 7tws, 7tx4, 7tx5

Cited: 16 times
EuropePMC logo PMID: 35622909

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)

  1. Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2. Gahbauer S, Correy GJ, Schuller M, Ferla MP, Doruk YU, Rachman M, Wu T, Diolaiti M, Wang S, Neitz RJ, Fearon D, Radchenko DS, Moroz YS, Irwin JJ, Renslo AR, Taylor JC, Gestwicki JE, von Delft F, Ashworth A, Ahel I, Shoichet BK, Fraser JS. Proc Natl Acad Sci U S A 120 e2212931120 (2023)
  2. Binding Adaptation of GS-441524 Diversifies Macro Domains and Downregulates SARS-CoV-2 de-MARylation Capacity. Tsika AC, Gallo A, Fourkiotis NK, Argyriou AI, Sreeramulu S, Löhr F, Rogov VV, Richter C, Linhard V, Gande SL, Altincekic N, Krishnathas R, Elamri I, Schwalbe H, Wollenhaupt J, Weiss MS, Spyroulias GA. J Mol Biol 434 167720 (2022)
  3. A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication in vivo. Taha TY, Suryawanshi RK, Chen IP, Correy GJ, McCavitt-Malvido M, O'Leary PC, Jogalekar MP, Diolaiti ME, Kimmerly GR, Tsou CL, Gascon R, Montano M, Martinez-Sobrido L, Krogan NJ, Ashworth A, Fraser JS, Ott M. PLoS Pathog 19 e1011614 (2023)
  4. SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice. Alhammad YM, Parthasarathy S, Ghimire R, Kerr CM, O'Connor JJ, Pfannenstiel JJ, Chanda D, Miller CA, Baumlin N, Salathe M, Unckless RL, Zuñiga S, Enjuanes L, More S, Channappanavar R, Fehr AR. Proc Natl Acad Sci U S A 120 e2302083120 (2023)
  5. A Fluorescence Polarization Assay for Macrodomains Facilitates the Identification of Potent Inhibitors of the SARS-CoV-2 Macrodomain. Anmangandla A, Jana S, Peng K, Wallace SD, Bagde SR, Drown BS, Xu J, Hergenrother PJ, Fromme JC, Lin H. ACS Chem Biol 18 1200-1207 (2023)
  6. Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors. Schuller M, Zarganes-Tzitzikas T, Bennett J, De Cesco S, Fearon D, von Delft F, Fedorov O, Brennan PE, Ahel I. Pathogens 12 324 (2023)
  7. PARP14 is a writer, reader, and eraser of mono-ADP-ribosylation. Torretta A, Chatzicharalampous C, Ebenwaldner C, Schüler H. J Biol Chem 299 105096 (2023)
  8. SARS-CoV-2 SUD2 and Nsp5 Conspire to Boost Apoptosis of Respiratory Epithelial Cells via an Augmented Interaction with the G-Quadruplex of BclII. Li Y, Yu Q, Huang R, Chen H, Ren H, Ma L, He Y, Li W. mBio 14 e0335922 (2023)
  9. Structure-Based High-Throughput Virtual Screening and Molecular Dynamics Simulation for the Discovery of Novel SARS-CoV-2 NSP3 Mac1 Domain Inhibitors. Yazdani B, Sirous H, Brogi S, Calderone V. Viruses 15 2291 (2023)


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