7TWQ

Crystal structure of SARS-CoV-2 NSP3 macrodomain at pH 9 (P43 crystal form)

7TWQ の概要

• エントリーDOI: 10.2210/pdb7twq/pdb
• 分子名称: Non-structural protein 3 (2 entities in total)
• 機能のキーワード: sars-cov-2, room temperature diffraction, protein dynamics, water networks, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 36357.53

構造登録者

Correy, G.J.,Fraser, J.S. (登録日: 2022-02-07, 公開日: 2022-02-23, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (0.9 Å)