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Article ; Online: Amino Acid Polymorphisms on the Brazilian Strain of Yellow Fever Virus Methyltransferase Are Related to the Host's Immune Evasion Mediated by Type I Interferon.

Furtado, Nathália Dias / de Mello, Iasmim Silva / de Godoy, Andre Schutzer / Noske, Gabriela Dias / Oliva, Glaucius / Canard, Bruno / Decroly, Etienne / Bonaldo, Myrna C

Viruses

2023 Volume 15, Issue 1

Abstract: Since late 2016, a yellow fever virus (YFV) variant carrying a set of nine amino acid variations has circulated in South America. Three of them were mapped on the methyltransferase (MTase) domain of viral NS5 protein. To assess whether these changes ... ...

Abstract	Since late 2016, a yellow fever virus (YFV) variant carrying a set of nine amino acid variations has circulated in South America. Three of them were mapped on the methyltransferase (MTase) domain of viral NS5 protein. To assess whether these changes affected viral infectivity, we synthesized YFV carrying the MTase of circulating lineage as well as its isoform with the residues of the previous strains (NS5 K101R, NS5 V138I, and NS5 G173S). We observed a slight difference in viral growth properties and plaque phenotype between the two synthetic YFVs. However, the MTase polymorphisms associated with the Brazilian strain of YFV (2016-2019) confer more susceptibility to the IFN-I. In addition, in vitro MTase assay revealed that the interaction between the YFV MTase and the methyl donor molecule (SAM) is altered in the Brazilian MTase variant. Altogether, the results reported here describe that the MTase carrying the molecular signature of the Brazilian YFV circulating since 2016 might display a slight decrease in its catalytic activity but virtually no effect on viral fitness in the parameters comprised in this study. The most marked influence of these residues stands in the immune escape against the antiviral response mediated by IFN-I.
MeSH term(s)	Yellow fever virus/physiology ; Interferon Type I/genetics ; Amino Acids ; Immune Evasion ; Brazil ; Methyltransferases/metabolism ; Viral Nonstructural Proteins/genetics
Chemical Substances	Interferon Type I ; Amino Acids ; Methyltransferases (EC 2.1.1.-) ; Viral Nonstructural Proteins
Language	English
Publishing date	2023-01-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15010191
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Article ; Online: An in-solution snapshot of SARS-COV-2 main protease maturation process and inhibition.

Noske, Gabriela Dias / Song, Yun / Fernandes, Rafaela Sachetto / Chalk, Rod / Elmassoudi, Haitem / Koekemoer, Lizbé / Owen, C David / El-Baba, Tarick J / Robinson, Carol V / Oliva, Glaucius / Godoy, Andre Schutzer

Nature communications

2023 Volume 14, Issue 1, Page(s) 1545

Abstract: The main protease from SARS-CoV-2 ( ... ...

Abstract	The main protease from SARS-CoV-2 (M
MeSH term(s)	Antiviral Agents ; Protease Inhibitors/pharmacology ; SARS-CoV-2/enzymology ; Coronavirus 3C Proteases/chemistry
Chemical Substances	3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Antiviral Agents ; Protease Inhibitors ; Coronavirus 3C Proteases (EC 3.4.22.28)
Language	English
Publishing date	2023-03-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-37035-5
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Article ; Online: Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease.

Noske, Gabriela Dias / de Souza Silva, Ellen / de Godoy, Mariana Ortiz / Dolci, Isabela / Fernandes, Rafaela Sachetto / Guido, Rafael Victório Carvalho / Sjö, Peter / Oliva, Glaucius / Godoy, Andre Schutzer

The Journal of biological chemistry

2023 Volume 299, Issue 3, Page(s) 103004

Abstract: SARS-CoV-2 is the causative agent of COVID-19. The main viral protease ( ... ...

Abstract	SARS-CoV-2 is the causative agent of COVID-19. The main viral protease (M
MeSH term(s)	Humans ; COVID-19/genetics ; SARS-CoV-2/genetics ; Antiviral Agents/pharmacology ; Lactams ; Leucine ; Nitriles ; Protease Inhibitors/pharmacology
Chemical Substances	3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; ensitrelvir (PX665RAA3H) ; Antiviral Agents ; Lactams ; Leucine (GMW67QNF9C) ; Nitriles ; Protease Inhibitors
Language	English
Publishing date	2023-02-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.103004
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Article ; Online: Structural characterization and polymorphism analysis of the NS2B-NS3 protease from the 2017 Brazilian circulating strain of Yellow Fever virus.

Noske, Gabriela Dias / Gawriljuk, Victor Oliveira / Fernandes, Rafaela Sachetto / Furtado, Nathalia Dias / Bonaldo, Myrna Cristina / Oliva, Glaucius / Godoy, Andre Schutzer

Biochimica et biophysica acta. General subjects

2020 Volume 1864, Issue 4, Page(s) 129521

Abstract: Background: The Yellow Fever virus (YFV) is transmitted by mosquitos and causes an infection with symptoms including fever, headaches and nausea. In 20-50% of the cases, the disease may evolve to a visceral stage, reaching high mortality rates. YFV NS2B- ...

Abstract	Background: The Yellow Fever virus (YFV) is transmitted by mosquitos and causes an infection with symptoms including fever, headaches and nausea. In 20-50% of the cases, the disease may evolve to a visceral stage, reaching high mortality rates. YFV NS2B-NS3 protease has been identified as an important drug target. Methods: Herein, we describe the crystal structure of the NS2B-NS3 protease from the 2017 YFV Brazilian circulating strain using X-ray crystallography. Furthermore, we used a combination of biochemical and biophysical assays to characterize the enzyme and investigate the impact of the polymorphisms observed in different YFV circulating strains. Results: Surprisingly, the crystal structure of YFV protease seems to adopt the closed conformation without the presence of a binding partner. Although D88E and K121R mutants exhibited a lower affinity for the substrate, both revealed to be more processive, resulting in a similar catalytic efficiency in relation to the WT protease. Still, both mutants showed an accentuated decrease in stability when compared with the WT. Conclusions: The crystal structure of YFV NS2B-NS3 in closed conformation might be an important tool for the development of new drugs, as well as understanding the activation mechanism of viral proteases. Biochemical analyses indicate that the NS2B-NS3 protease of the circulating strain of YFV is more stable than previous strains. General significance: The YFV NS2B-NS3 protease is the first flaviviral structure described in its closed conformation when in a free form, implying that external factors might induce the activation of the enzyme.
MeSH term(s)	Brazil ; Models, Molecular ; Mutagenesis, Site-Directed ; Polymorphism, Single Nucleotide/genetics ; Protein Conformation ; RNA Helicases/chemistry ; RNA Helicases/genetics ; RNA Helicases/metabolism ; Serine Endopeptidases/chemistry ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism ; Yellow fever virus/enzymology
Chemical Substances	NS2B protein, flavivirus ; NS3 protein, flavivirus ; Viral Nonstructural Proteins ; Serine Endopeptidases (EC 3.4.21.-) ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2020-01-10
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbagen.2020.129521
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Article ; Online: Enzymatic versatility and thermostability of a new aryl-alcohol oxidase from Thermothelomyces thermophilus M77.

Kadowaki, Marco Antonio Seiki / Higasi, Paula Miwa Rabelo / de Godoy, Mariana Ortiz / de Araújo, Evandro Ares / Godoy, Andre Schutzer / Prade, Rolf Alexander / Polikarpov, Igor

Biochimica et biophysica acta. General subjects

2020 Volume 1864, Issue 10, Page(s) 129681

Abstract: Background Fungal aryl-alcohol oxidases (AAOx) are extracellular flavoenzymes that belong to glucose-methanol-choline oxidoreductase family and are responsible for the selective conversion of primary aromatic alcohols into aldehydes and aromatic ... ...

Abstract	Background Fungal aryl-alcohol oxidases (AAOx) are extracellular flavoenzymes that belong to glucose-methanol-choline oxidoreductase family and are responsible for the selective conversion of primary aromatic alcohols into aldehydes and aromatic aldehydes to their corresponding acids, with concomitant production of hydrogen peroxide (H
MeSH term(s)	Alcohol Oxidoreductases/chemistry ; Alcohol Oxidoreductases/metabolism ; Ascomycota/chemistry ; Ascomycota/enzymology ; Ascomycota/metabolism ; Binding Sites ; Calcium/metabolism ; Crystallography, X-Ray ; Enzyme Stability ; Hydrogen Peroxide/metabolism ; Models, Molecular ; Protein Conformation ; Substrate Specificity ; Temperature
Chemical Substances	Hydrogen Peroxide (BBX060AN9V) ; Alcohol Oxidoreductases (EC 1.1.-) ; aryl-alcohol oxidase (EC 1.1.3.7) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2020-07-10
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbagen.2020.129681
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Article: Enzymatic versatility and thermostability of a new aryl-alcohol oxidase from Thermothelomyces thermophilus M77

Kadowaki, Marco Antonio Seiki / Higasi, Paula Miwa Rabelo / de Godoy, Mariana Ortiz / de Araújo, Evandro Ares / Godoy, Andre Schutzer / Prade, Rolf Alexander / Polikarpov, Igor

Biochimica et biophysica acta. 2020 Oct., v. 1864, no. 10

2020

Abstract: BackgroundFungal aryl-alcohol oxidases (AAOx) are extracellular flavoenzymes that belong to glucose-methanol-choline oxidoreductase family and are responsible for the selective conversion of primary aromatic alcohols into aldehydes and aromatic aldehydes ...

Abstract	BackgroundFungal aryl-alcohol oxidases (AAOx) are extracellular flavoenzymes that belong to glucose-methanol-choline oxidoreductase family and are responsible for the selective conversion of primary aromatic alcohols into aldehydes and aromatic aldehydes to their corresponding acids, with concomitant production of hydrogen peroxide (H₂O₂) as by-product. The H₂O₂ can be provided to lignin degradation pathway, a biotechnological property explored in biofuel production. In the thermophilic fungus Thermothelomyces thermophilus (formerly Myceliophthora thermophila), just one AAOx was identified in the exo-proteome.MethodsThe glycosylated and non-refolded crystal structure of an AAOx from T. thermophilus at 2.6 Å resolution was elucidated by X-ray crystallography combined with small-angle X-ray scattering (SAXS) studies. Moreover, biochemical analyses were carried out to shed light on enzyme substrate specificity and thermostability.ResultsThis flavoenzyme harbors a flavin adenine dinucleotide as a cofactor and is able to oxidize aromatic substrates and 5-HMF. Our results also show that the enzyme has similar oxidation rates for bulky or simple aromatic substrates such as cinnamyl and veratryl alcohols. Moreover, the crystal structure of MtAAOx reveals an open active site, which might explain observed specificity of the enzyme.ConclusionsMtAAOx shows previously undescribed structural differences such as a fully accessible catalytic tunnel, heavy glycosylation and Ca²⁺ binding site providing evidences for thermostability and activity of the enzymes from AA3_2 subfamily.General significanceStructural and biochemical analyses of MtAAOx could be important for comprehension of aryl-alcohol oxidases structure-function relationships and provide additional molecular tools to be used in future biotechnological applications.
Keywords	Myceliophthora thermophila ; X-ray diffraction ; acids ; active sites ; alcohols ; aldehydes ; aryl-alcohol oxidase ; binding sites ; calcium ; catalytic activity ; crystal structure ; enzyme activity ; enzyme substrates ; flavin-adenine dinucleotide ; fuel production ; glycosylation ; hydrogen peroxide ; lignin ; oxidation ; small-angle X-ray scattering ; structure-activity relationships ; substrate specificity ; thermal stability ; thermophilic fungi
Language	English
Dates of publication	2020-10
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	840755-1
ISSN	0304-4165
ISSN	0304-4165
DOI	10.1016/j.bbagen.2020.129681
Database	NAL-Catalogue (AGRICOLA)

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Article: Structural characterization and polymorphism analysis of the NS2B-NS3 protease from the 2017 Brazilian circulating strain of Yellow Fever virus

Noske, Gabriela Dias / Gawriljuk, Victor Oliveira / Fernandes, Rafaela Sachetto / Furtado, Nathalia Dias / Bonaldo, Myrna Cristina / Oliva, Glaucius / Godoy, Andre Schutzer

Biochimica et biophysica acta. 2020 Apr., v. 1864, no. 4

2020

Abstract: The Yellow Fever virus (YFV) is transmitted by mosquitos and causes an infection with symptoms including fever, headaches and nausea. In 20–50% of the cases, the disease may evolve to a visceral stage, reaching high mortality rates. YFV NS2B-NS3 protease ...

Abstract	The Yellow Fever virus (YFV) is transmitted by mosquitos and causes an infection with symptoms including fever, headaches and nausea. In 20–50% of the cases, the disease may evolve to a visceral stage, reaching high mortality rates. YFV NS2B-NS3 protease has been identified as an important drug target.Herein, we describe the crystal structure of the NS2B-NS3 protease from the 2017 YFV Brazilian circulating strain using X-ray crystallography. Furthermore, we used a combination of biochemical and biophysical assays to characterize the enzyme and investigate the impact of the polymorphisms observed in different YFV circulating strains.Surprisingly, the crystal structure of YFV protease seems to adopt the closed conformation without the presence of a binding partner. Although D88E and K121R mutants exhibited a lower affinity for the substrate, both revealed to be more processive, resulting in a similar catalytic efficiency in relation to the WT protease. Still, both mutants showed an accentuated decrease in stability when compared with the WT.The crystal structure of YFV NS2B-NS3 in closed conformation might be an important tool for the development of new drugs, as well as understanding the activation mechanism of viral proteases. Biochemical analyses indicate that the NS2B-NS3 protease of the circulating strain of YFV is more stable than previous strains.The YFV NS2B-NS3 protease is the first flaviviral structure described in its closed conformation when in a free form, implying that external factors might induce the activation of the enzyme.
Keywords	Culicidae ; X-ray diffraction ; Yellow fever virus ; catalytic activity ; crystal structure ; fever ; headache ; mortality ; mutants ; nausea ; proteinases
Language	English
Dates of publication	2020-04
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	840755-1
ISSN	0304-4165
ISSN	0304-4165
DOI	10.1016/j.bbagen.2020.129521
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Article ; Online: Discovery of an imidazonaphthyridine and a riminophenazine as potent anti-Zika virus agents through a replicon-based high-throughput screening.

Fernandes, Rafaela Sachetto / de Godoy, Andre Schutzer / Santos, Igor Andrade / Noske, Gabriela Dias / de Oliveira, Ketllyn Irene Zagato / Gawriljuk, Victor Oliveira / Gomes Jardim, Ana Carolina / Oliva, Glaucius

Virus research

2021 Volume 299, Page(s) 198388

Abstract: The 2015/16 Zika virus (ZIKV) epidemic led to almost 1 million confirmed cases in 84 countries and was associated to the development of congenital microcephaly and Guillain-Barré syndrome. More recently, a ZIKV African lineage was identified in Brazil ... ...

Abstract	The 2015/16 Zika virus (ZIKV) epidemic led to almost 1 million confirmed cases in 84 countries and was associated to the development of congenital microcephaly and Guillain-Barré syndrome. More recently, a ZIKV African lineage was identified in Brazil raising concerns about a future outbreak. The long-term consequences of viral infection emphasizes the need for the development of effective anti-ZIKV drugs. In this study, we developed and characterized a ZIKV replicon cell line for the screening of viral replication inhibitors. The replicon system was developed by engineering the IRES-Neo cassette into the 3' UTR terminus of the ZIKV Rluc DNA construct. After in vitro transcription, replicon RNA was used to transfect BHK-21 cells, that were selected with G418, thus generating the BHK-21-RepZIKV_IRES-Neo cell line. Through this replicon-based cell system, we identified two molecules with potent anti-ZIKV activities, an imidazonaphthyridine and a riminophenazine, both from the MMV/DNDi Pandemic Response Box library of 400 drug-like compounds. The imidazonaphthyridine, known as RO8191, showed remarkable selectivity against ZIKV, while the riminophenazine, the antibiotic Clofazimine, could act as a non-nucleoside analog inhibitor of viral RNA-dependent RNA polymerase (RdRp), as evidenced both in vitro and in silico. The data showed herein supports the use of replicon-based assays in high-throughput screening format as a biosafe and reliable tool for antiviral drug discovery.
MeSH term(s)	Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Clofazimine/pharmacology ; Clofazimine/therapeutic use ; High-Throughput Screening Assays ; Humans ; Replicon ; Virus Replication ; Zika Virus/physiology ; Zika Virus Infection
Chemical Substances	Antiviral Agents ; Clofazimine (D959AE5USF)
Language	English
Publishing date	2021-04-20
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2021.198388
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Article ; Online: Imidazonaphthyridine effects on Chikungunya virus replication: Antiviral activity by dependent and independent of interferon type 1 pathways.

Ruiz, Uriel Enrique Aquino / Santos, Igor Andrade / Grosche, Victória Riquena / Fernandes, Rafaela Sachetto / de Godoy, Andre Schutzer / Torres, Jhoan David Aguillón / Freire, Marjorie Caroline Liberato Cavalcanti / Mesquita, Nathalya Cristina de Moraes Roso / Guevara-Vega, Marco / Nicolau-Junior, Nilson / Sabino-Silva, Robinson / Mineo, Tiago Wilson Patriarca / Oliva, Glaucius / Jardim, Ana Carolina Gomes

Virus research

2022 Volume 324, Page(s) 199029

Abstract: The Chikungunya virus (CHIKV) causes Chikungunya fever, a disease characterized by symptoms such as arthralgia/polyarthralgia. Currently, there are no antivirals approved against CHIKV, emphasizing the need to develop novel therapies. The ... ...

Abstract	The Chikungunya virus (CHIKV) causes Chikungunya fever, a disease characterized by symptoms such as arthralgia/polyarthralgia. Currently, there are no antivirals approved against CHIKV, emphasizing the need to develop novel therapies. The imidazonaphthyridine compound (RO8191), an interferon-α (IFN-α) agonist, was reported as a potent inhibitor of HCV. Here RO8191 was investigated for its potential to inhibit CHIKV replication in vitro. RO8191 inhibited CHIKV infection in BHK-21 and Vero-E6 cells with a selectivity index (SI) of 12.3 and 37.3, respectively. Additionally, RO8191 was capable to protect cells against CHIKV infection, inhibit entry by virucidal activity, and strongly impair post-entry steps of viral replication. An effect of RO8191 on CHIKV replication was demonstrated in BHK-21 through type-1 IFN production mechanism and in Vero-E6 cells which has a defective type-1 IFN production, also suggesting a type-1 IFN independent mode of action. Molecular docking calculations demonstrated interactions of RO8191 with the CHIKV E proteins, corroborated by the ATR-FTIR assay, and with non-structural proteins, supported by the CHIKV-subgenomic replicon cells assay.
MeSH term(s)	Animals ; Chlorocebus aethiops ; Humans ; Chikungunya virus ; Chikungunya Fever/drug therapy ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Molecular Docking Simulation ; Virus Replication ; Vero Cells ; Interferon Type I/pharmacology
Chemical Substances	Antiviral Agents ; Interferon Type I
Language	English
Publishing date	2022-12-22
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2022.199029
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Article ; Online: Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease.

Godoy, Andre Schutzer / Nakamura, Aline Minalli / Douangamath, Alice / Song, Yun / Noske, Gabriela Dias / Gawriljuk, Victor Oliveira / Fernandes, Rafaela Sachetto / Pereira, Humberto D Muniz / Oliveira, Ketllyn Irene Zagato / Fearon, Daren / Dias, Alexandre / Krojer, Tobias / Fairhead, Michael / Powell, Alisa / Dunnet, Louise / Brandao-Neto, Jose / Skyner, Rachael / Chalk, Rod / Bajusz, Dávid /

Bege, Miklós / Borbás, Anikó / Keserű, György Miklós / von Delft, Frank / Oliva, Glaucius

Nucleic acids research

2023 Volume 51, Issue 10, Page(s) 5255–5270

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 ... ...

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.
MeSH term(s)	Humans ; Allosteric Regulation ; Amino Acid Sequence ; COVID-19 ; Cryoelectron Microscopy ; Endoribonucleases/metabolism ; SARS-CoV-2/metabolism ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/chemistry
Chemical Substances	Endoribonucleases (EC 3.1.-) ; Viral Nonstructural Proteins ; nidoviral uridylate-specific endoribonuclease (EC 3.1.-)
Language	English
Publishing date	2023-04-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad314
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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