دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease.
المؤلفون: Godoy AS; Sao Carlos Institute of Physics, University of Sao Paulo, Av. Joao Dagnone, 1100 - Jardim Santa Angelina, Sao Carlos, 13563-120, Brazil., Nakamura AM; Sao Carlos Institute of Physics, University of Sao Paulo, Av. Joao Dagnone, 1100 - Jardim Santa Angelina, Sao Carlos, 13563-120, Brazil., Douangamath A; Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot OX11 0QX, UK.; Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK., Song Y; Electron Bio-imaging Centre, Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0QX, UK., Noske GD; Sao Carlos Institute of Physics, University of Sao Paulo, Av. Joao Dagnone, 1100 - Jardim Santa Angelina, Sao Carlos, 13563-120, Brazil., Gawriljuk VO; Sao Carlos Institute of Physics, University of Sao Paulo, Av. Joao Dagnone, 1100 - Jardim Santa Angelina, Sao Carlos, 13563-120, Brazil., Fernandes RS; Sao Carlos Institute of Physics, University of Sao Paulo, Av. Joao Dagnone, 1100 - Jardim Santa Angelina, Sao Carlos, 13563-120, Brazil., Pereira HDM; Sao Carlos Institute of Physics, University of Sao Paulo, Av. Joao Dagnone, 1100 - Jardim Santa Angelina, Sao Carlos, 13563-120, Brazil., Oliveira KIZ; Sao Carlos Institute of Physics, University of Sao Paulo, Av. Joao Dagnone, 1100 - Jardim Santa Angelina, Sao Carlos, 13563-120, Brazil., Fearon D; Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot OX11 0QX, UK.; Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK., Dias A; Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot OX11 0QX, UK.; Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK., Krojer T; BioMAX, MAX IV Laboratory, Fotongatan 2, Lund 224 84, Sweden., Fairhead M; Centre for Medicines Discovery, Oxford University, Oxford OX1 3QU, UK., Powell A; Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot OX11 0QX, UK.; Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK., Dunnet L; Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot OX11 0QX, UK.; Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK., Brandao-Neto J; Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot OX11 0QX, UK.; Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK., Skyner R; Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot OX11 0QX, UK.; Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK., Chalk R; Centre for Medicines Discovery, Oxford University, Oxford OX1 3QU, UK., Bajusz D; Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary., Bege M; Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.; MTA-DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary., Borbás A; Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.; National Laboratory of Virology, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary., Keserű GM; Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary., von Delft F; Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot OX11 0QX, UK.; Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK.; Centre for Medicines Discovery, Oxford University, Oxford OX1 3QU, UK.; Department of Biochemistry, University of Johannesburg, PO Box 524, Auckland Park 2006, South Africa., Oliva G; Sao Carlos Institute of Physics, University of Sao Paulo, Av. Joao Dagnone, 1100 - Jardim Santa Angelina, Sao Carlos, 13563-120, Brazil.
المصدر: Nucleic acids research [Nucleic Acids Res] 2023 Jun 09; Vol. 51 (10), pp. 5255-5270.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.
مواضيع طبية MeSH: SARS-CoV-2*/metabolism, Humans ; Allosteric Regulation ; Amino Acid Sequence ; COVID-19 ; Cryoelectron Microscopy ; Endoribonucleases/metabolism ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/chemistry
مستخلص: 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.
(© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; U19 AI171399 United States AI NIAID NIH HHS
المشرفين على المادة: EC 3.1.- (Endoribonucleases)
0 (Viral Nonstructural Proteins)
EC 3.1.- (nidoviral uridylate-specific endoribonuclease)
تواريخ الأحداث: Date Created: 20230428 Date Completed: 20230614 Latest Revision: 20240630
رمز التحديث: 20240630
مُعرف محوري في PubMed: PMC10250223
DOI: 10.1093/nar/gkad314
PMID: 37115000
قاعدة البيانات: MEDLINE
الوصف
تدمد:1362-4962
DOI:10.1093/nar/gkad314