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Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength) Krios II-Titan Krios II at Diamond	Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease Andre Schutzer Godoy , Aline Minalli Nakamura , Alice Douangamath , Yun Song , Gabriela Dias Noske , Victor Oliveira Gawriljuk , Rafaela Sachetto Fernandes , Humberto D'Muniz Pereira , Ketllyn irene Zagato Oliveira , Daren Fearon , Alexandre Dias , Tobias Krojer , Michael Fairhead , Alisa Powell , Louise Dunnett , Jose Brandao-Neto , Rachael Skyner , Rod Chalk , Dávid Bajusz , Miklós Bege , Anikó Borbás , György Miklós Keserű , Frank Von Delft , Glaucius Oliva Nucleic Acids Research 579 DOI: 10.1093/nar/gkad314 Diamond Proposal Number(s): [27083, 27023] Open Access Show Abstract ▼ Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The NSP15 endoribonuclease enzyme, known as NendoU, is highly conserved and plays a critical role in the ability of the virus to evade the immune system. NendoU is a promising target for the development of new antiviral drugs. However, the complexity of the enzyme's structure and kinetics, along with the broad range of recognition sequences and lack of structural complexes, hampers the development of inhibitors. Here, we performed enzymatic characterization of NendoU in its monomeric and hexameric form, showing that hexamers are allosteric enzymes with a positive cooperative index, and with no influence of manganese on enzymatic activity. Through combining cryo-electron microscopy at different pHs, X-ray crystallography and biochemical and structural analysis, we showed that NendoU can shift between open and closed forms, which probably correspond to active and inactive states, respectively. We also explored the possibility of NendoU assembling into larger supramolecular structures and proposed a mechanism for allosteric regulation. In addition, we conducted a large fragment screening campaign against NendoU and identified several new allosteric sites that could be targeted for the development of new inhibitors. Overall, our findings provide insights into the complex structure and function of NendoU and offer new opportunities for the development of inhibitors.	Apr 2023

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I04-1-Macromolecular Crystallography (fixed wavelength)
Krios II-Titan Krios II at Diamond

Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease