7TX5

Neutron crystal structure of SARS-CoV-2 NSP3 macrodomain in complex with ADP-ribose at 293 K (C2 crystal form)

Summary for 7TX5

• Entry DOI: 10.2210/pdb7tx5/pdb
• Descriptor: Papain-like protease nsp3, ADENOSINE-5-DIPHOSPHORIBOSE (3 entities in total)
• Functional Keywords: sars-cov-2, room temperature diffraction, protein dynamics, water networks, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 18778.04

Authors

Correy, G.J.,Fraser, J.S.,Kovalevsky, A. (deposition date: 2022-02-07, release date: 2022-02-23, Last modification date: 2023-10-25)

Primary citation

Correy, G.J.,Kneller, D.W.,Phillips, G.,Pant, S.,Russi, S.,Cohen, A.E.,Meigs, G.,Holton, J.M.,Gahbauer, S.,Thompson, M.C.,Ashworth, A.,Coates, L.,Kovalevsky, A.,Meilleur, F.,Fraser, J.S.
The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and x-ray diffraction at room temperature.
Sci Adv, 8:eabo5083-eabo5083, 2022

PubMed 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.

PubMed: 35622909
DOI: 10.1126/sciadv.abo5083

Experimental method

NEUTRON DIFFRACTION (2.3 Å)
X-RAY DIFFRACTION (1.95 Å)