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Article ; Online: Evolution of the SARS-CoV-2 spike protein in the human host.

Wrobel, Antoni G / Benton, Donald J / Roustan, Chloë / Borg, Annabel / Hussain, Saira / Martin, Stephen R / Rosenthal, Peter B / Skehel, John J / Gamblin, Steven J

Nature communications

2022 Volume 13, Issue 1, Page(s) 1178

Abstract: Recently emerged variants of SARS-CoV-2 contain in their surface spike glycoproteins multiple substitutions associated with increased transmission and resistance to neutralising antibodies. We have examined the structure and receptor binding properties ... ...

Abstract	Recently emerged variants of SARS-CoV-2 contain in their surface spike glycoproteins multiple substitutions associated with increased transmission and resistance to neutralising antibodies. We have examined the structure and receptor binding properties of spike proteins from the B.1.1.7 (Alpha) and B.1.351 (Beta) variants to better understand the evolution of the virus in humans. Spikes of both variants have the same mutation, N501Y, in the receptor-binding domains. This substitution confers tighter ACE2 binding, dependent on the common earlier substitution, D614G. Each variant spike has acquired other key changes in structure that likely impact virus pathogenesis. The spike from the Alpha variant is more stable against disruption upon binding ACE2 receptor than all other spikes studied. This feature is linked to the acquisition of a more basic substitution at the S1-S2 furin site (also observed for the variants of concern Delta, Kappa, and Omicron) which allows for near-complete cleavage. In the Beta variant spike, the presence of a new substitution, K417N (also observed in the Omicron variant), in combination with the D614G, stabilises a more open spike trimer, a conformation required for receptor binding. Our observations suggest ways these viruses have evolved to achieve greater transmissibility in humans.
MeSH term(s)	Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/metabolism ; Angiotensin-Converting Enzyme 2/ultrastructure ; Binding Sites/genetics ; COVID-19/metabolism ; COVID-19/transmission ; COVID-19/virology ; Cryoelectron Microscopy ; Cytopathogenic Effect, Viral/genetics ; Evolution, Molecular ; Host-Pathogen Interactions ; Humans ; Kinetics ; Models, Molecular ; Mutation, Missense ; Protein Binding ; Protein Domains ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2022-03-04
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/s41467-022-28768-w
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Article ; Online: A KLK6 Activity-Based Probe Reveals a Role for KLK6 Activity in Pancreatic Cancer Cell Invasion.

Zhang, Leran / Lovell, Scott / De Vita, Elena / Jagtap, Pravin Kumar Ankush / Lucy, Daniel / Goya Grocin, Andrea / Kjær, Svend / Borg, Annabel / Hennig, Janosch / Miller, Aubry K / Tate, Edward W

Journal of the American Chemical Society

2022 Volume 144, Issue 49, Page(s) 22493–22504

Abstract: Pancreatic cancer has the lowest survival rate of all common cancers due to late diagnosis and limited treatment options. Serine hydrolases are known to mediate cancer progression and metastasis through initiation of signaling cascades and cleavage of ... ...

Abstract	Pancreatic cancer has the lowest survival rate of all common cancers due to late diagnosis and limited treatment options. Serine hydrolases are known to mediate cancer progression and metastasis through initiation of signaling cascades and cleavage of extracellular matrix proteins, and the kallikrein-related peptidase (KLK) family of secreted serine proteases have emerging roles in pancreatic ductal adenocarcinoma (PDAC). However, the lack of reliable activity-based probes (ABPs) to profile KLK activity has hindered progress in validation of these enzymes as potential targets or biomarkers. Here, we developed potent and selective ABPs for KLK6 by using a positional scanning combinatorial substrate library and characterized their binding mode and interactions by X-ray crystallography. The optimized KLK6 probe IMP-2352 (
MeSH term(s)	Humans ; Pancreatic Neoplasms ; Kallikreins/metabolism ; Carcinoma, Pancreatic Ductal ; Neoplasm Invasiveness ; Pancreatic Neoplasms
Chemical Substances	Kallikreins (EC 3.4.21.-) ; KLK6 protein, human (EC 3.4.21.-)
Language	English
Publishing date	2022-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.2c07378
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Article: O-Linked Sialoglycans Modulate the Proteolysis of SARS-CoV-2 Spike and Likely Contribute to the Mutational Trajectory in Variants of Concern.

ACS central science

2023 Volume 9, Issue 3, Page(s) 393–404

Abstract: The emergence of a polybasic cleavage motif for the protease furin in SARS-CoV-2 spike has been established as a major factor for human viral transmission. The region N-terminal to that motif is extensively mutated in variants of concern (VOCs). Besides ... ...

Abstract	The emergence of a polybasic cleavage motif for the protease furin in SARS-CoV-2 spike has been established as a major factor for human viral transmission. The region N-terminal to that motif is extensively mutated in variants of concern (VOCs). Besides furin, spikes from these variants appear to rely on other proteases for maturation, including TMPRSS2. Glycans near the cleavage site have raised questions about proteolytic processing and the consequences of variant-borne mutations. Here, we identify that sialic acid-containing O-linked glycans on Thr678 of SARS-CoV-2 spike influence furin and TMPRSS2 cleavage and posit O-linked glycosylation as a likely driving force for the emergence of VOC mutations. We provide direct evidence that the glycosyltransferase GalNAc-T1 primes glycosylation at Thr678 in the living cell, an event that is suppressed by mutations in the VOCs Alpha, Delta, and Omicron. We found that the sole incorporation of
Language	English
Publishing date	2023-02-16
Publishing country	United States
Document type	Journal Article
ISSN	2374-7943
ISSN	2374-7943
DOI	10.1021/acscentsci.2c01349
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Article ; Online: The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2.

Benton, Donald J / Wrobel, Antoni G / Roustan, Chloë / Borg, Annabel / Xu, Pengqi / Martin, Stephen R / Rosenthal, Peter B / Skehel, John J / Gamblin, Steven J

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 9

Abstract: The majority of currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses have mutant spike glycoproteins that contain the D614G substitution. Several studies have suggested that spikes with this substitution are ... ...

Abstract	The majority of currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses have mutant spike glycoproteins that contain the D614G substitution. Several studies have suggested that spikes with this substitution are associated with higher virus infectivity. We use cryo-electron microscopy to compare G614 and D614 spikes and show that the G614 mutant spike adopts a range of more open conformations that may facilitate binding to the SARS-CoV-2 receptor, ACE2, and the subsequent structural rearrangements required for viral membrane fusion.
MeSH term(s)	COVID-19/virology ; Cryoelectron Microscopy ; Humans ; Protein Conformation ; SARS-CoV-2/chemistry ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Virus Internalization
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-02-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2022586118
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Article ; Online: Structure and binding properties of Pangolin-CoV spike glycoprotein inform the evolution of SARS-CoV-2.

Wrobel, Antoni G / Benton, Donald J / Xu, Pengqi / Calder, Lesley J / Borg, Annabel / Roustan, Chloë / Martin, Stephen R / Rosenthal, Peter B / Skehel, John J / Gamblin, Steven J

Nature communications

2021 Volume 12, Issue 1, Page(s) 837

Abstract: Coronaviruses of bats and pangolins have been implicated in the origin and evolution of the pandemic SARS-CoV-2. We show that spikes from Guangdong Pangolin-CoVs, closely related to SARS-CoV-2, bind strongly to human and pangolin ACE2 receptors. We also ... ...

Abstract	Coronaviruses of bats and pangolins have been implicated in the origin and evolution of the pandemic SARS-CoV-2. We show that spikes from Guangdong Pangolin-CoVs, closely related to SARS-CoV-2, bind strongly to human and pangolin ACE2 receptors. We also report the cryo-EM structure of a Pangolin-CoV spike protein and show it adopts a fully-closed conformation and that, aside from the Receptor-Binding Domain, it resembles the spike of a bat coronavirus RaTG13 more than that of SARS-CoV-2.
MeSH term(s)	Angiotensin-Converting Enzyme 2/metabolism ; Animals ; Binding, Competitive ; COVID-19/epidemiology ; COVID-19/prevention & control ; COVID-19/virology ; Cryoelectron Microscopy ; Evolution, Molecular ; Humans ; Models, Molecular ; Pandemics ; Pangolins/virology ; Protein Binding ; Protein Domains ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-02-05
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/s41467-021-21006-9
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Article ; Online: A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing.

Adams, Sarah E / Purkiss, Andrew G / Knowles, Phillip P / Nans, Andrea / Briggs, David C / Borg, Annabel / Earl, Christopher P / Goodman, Kerry M / Nawrotek, Agata / Borg, Aaron J / McIntosh, Pauline B / Houghton, Francesca M / Kjær, Svend / McDonald, Neil Q

Structure (London, England : 1993)

2021 Volume 29, Issue 7, Page(s) 694–708.e7

Abstract: RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFRα co-receptors recognize and activate RET stimulating its cytoplasmic kinase function. The principles for ... ...

Abstract	RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFRα co-receptors recognize and activate RET stimulating its cytoplasmic kinase function. The principles for RET ligand-co-receptor recognition are incompletely understood. Here, we report a crystal structure of the cadherin-like module (CLD1-4) from zebrafish RET revealing interdomain flexibility between CLD2 and CLD3. Comparison with a cryo-electron microscopy structure of a ligand-engaged zebrafish RET
MeSH term(s)	Animals ; Cadherins/metabolism ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism ; Models, Molecular ; Multiprotein Complexes/chemistry ; Protein Binding ; Protein Conformation ; Protein Domains ; Proto-Oncogene Proteins c-ret/chemistry ; Proto-Oncogene Proteins c-ret/metabolism ; Zebrafish/metabolism ; Zebrafish Proteins/chemistry ; Zebrafish Proteins/metabolism
Chemical Substances	Cadherins ; Glial Cell Line-Derived Neurotrophic Factor ; Glial Cell Line-Derived Neurotrophic Factor Receptors ; Multiprotein Complexes ; Zebrafish Proteins ; gdnfa protein, zebrafish ; gfra1a protein, zebrafish ; Proto-Oncogene Proteins c-ret (EC 2.7.10.1) ; Ret protein, zebrafish (EC 2.7.10.1)
Language	English
Publishing date	2021-01-22
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2020.12.012
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Article ; Online: Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp13 helicase.

Zeng, Jingkun / Weissmann, Florian / Bertolin, Agustina P / Posse, Viktor / Canal, Berta / Ulferts, Rachel / Wu, Mary / Harvey, Ruth / Hussain, Saira / Milligan, Jennifer C / Roustan, Chloe / Borg, Annabel / McCoy, Laura / Drury, Lucy S / Kjaer, Svend / McCauley, John / Howell, Michael / Beale, Rupert / Diffley, John F X

The Biochemical journal

2021 Volume 478, Issue 13, Page(s) 2405–2423

Abstract: The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains ... ...

Abstract	The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains unclear, there is a need for therapeutics. Repurposing existing drugs represents a promising and potentially rapid opportunity to find novel antivirals against SARS-CoV-2. The virus encodes at least nine enzymatic activities that are potential drug targets. Here, we have expressed, purified and developed enzymatic assays for SARS-CoV-2 nsp13 helicase, a viral replication protein that is essential for the coronavirus life cycle. We screened a custom chemical library of over 5000 previously characterized pharmaceuticals for nsp13 inhibitors using a fluorescence resonance energy transfer-based high-throughput screening approach. From this, we have identified FPA-124 and several suramin-related compounds as novel inhibitors of nsp13 helicase activity in vitro. We describe the efficacy of these drugs using assays we developed to monitor SARS-CoV-2 growth in Vero E6 cells.
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Chlorocebus aethiops ; Drug Evaluation, Preclinical ; Enzyme Assays ; Fluorescence Resonance Energy Transfer ; High-Throughput Screening Assays ; RNA Helicases/antagonists & inhibitors ; RNA Helicases/metabolism ; Reproducibility of Results ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Suramin/pharmacology ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; Small Molecule Libraries ; Viral Nonstructural Proteins ; Suramin (6032D45BEM) ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20210201
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Article ; Online: Cysteine-Reactive Free ISG15 Generates IL-1β-Producing CD8α

Napolitano, Anna / van der Veen, Annemarthe G / Bunyan, Monique / Borg, Annabel / Frith, David / Howell, Steven / Kjaer, Svend / Beling, Antje / Snijders, Ambrosius P / Knobeloch, Klaus-Peter / Frickel, Eva-Maria

Journal of immunology (Baltimore, Md. : 1950)

2018 Volume 201, Issue 2, Page(s) 604–614

Abstract: IFN-stimulated gene (ISG) 15 is a ubiquitin-like protein induced after type I IFN stimulation. There is a dearth of in vivo models to study free unconjugated ISG15 function. We found that free ISG15 enhances the production of IFN-γ and IL-1β during ... ...

Abstract	IFN-stimulated gene (ISG) 15 is a ubiquitin-like protein induced after type I IFN stimulation. There is a dearth of in vivo models to study free unconjugated ISG15 function. We found that free ISG15 enhances the production of IFN-γ and IL-1β during murine infection with
MeSH term(s)	Animals ; CD8 Antigens/metabolism ; Cell Movement ; Cells, Cultured ; Cysteine/genetics ; Cytokines/genetics ; Cytokines/metabolism ; Dendritic Cells/immunology ; Disease Models, Animal ; Immunomodulation ; Interferon Type I/immunology ; Interferon-gamma/metabolism ; Interleukin-1beta/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Protein Conformation ; Toxoplasma/physiology ; Toxoplasmosis/immunology ; Ubiquitins/genetics ; Ubiquitins/metabolism
Chemical Substances	CD8 Antigens ; CD8alpha antigen ; Cytokines ; G1p2 protein, mouse ; Interferon Type I ; Interleukin-1beta ; Ubiquitins ; Interferon-gamma (82115-62-6) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2018-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1701322
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Ud II Zs.37: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The RIG-I-like receptor LGP2 inhibits Dicer-dependent processing of long double-stranded RNA and blocks RNA interference in mammalian cells.

van der Veen, Annemarthe G / Maillard, Pierre V / Schmidt, Jan Marten / Lee, Sonia A / Deddouche-Grass, Safia / Borg, Annabel / Kjær, Svend / Snijders, Ambrosius P / Reis e Sousa, Caetano

The EMBO journal

2018 Volume 37, Issue 4

Abstract: In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG-I-like receptor (RLR) family, which signal to induce production of type I interferons (IFN). These key antiviral cytokines act in a paracrine and autocrine manner to ...

Abstract	In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG-I-like receptor (RLR) family, which signal to induce production of type I interferons (IFN). These key antiviral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon-stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG-I, MDA5 and, the least-studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus-derived double-stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals, and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We show that LGP2 associates with Dicer and inhibits cleavage of dsRNA into siRNAs both
MeSH term(s)	DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/metabolism ; Gene Expression Regulation ; HeLa Cells ; Humans ; Interferon Type I/metabolism ; RNA Helicases/genetics ; RNA Helicases/metabolism ; RNA Interference ; RNA Viruses/physiology ; RNA, Double-Stranded/genetics ; RNA, Double-Stranded/metabolism ; RNA, Small Interfering/genetics ; RNA, Viral/genetics ; Ribonuclease III/genetics ; Ribonuclease III/metabolism ; Signal Transduction
Chemical Substances	Interferon Type I ; RNA, Double-Stranded ; RNA, Small Interfering ; RNA, Viral ; DHX58 protein, human (EC 2.7.7.-) ; DICER1 protein, human (EC 3.1.26.3) ; Ribonuclease III (EC 3.1.26.3) ; DEAD-box RNA Helicases (EC 3.6.4.13) ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2018-01-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.201797479
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Article ; Online: Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp13 Helicase

Beale, Rupert / Bertolin, Agustina P / Borg, Annabel / Canal, Berta / Diffley, John FX / Drury, Lucy S / Harvey, Ruth / Howell, Michael / Hussain, Saira / Kjaer, Svend / McCauley, John / McCoy, Laura / Milligan, Jennifer / Posse, Viktor / Roustan, Chloe / Ulferts, Rachel / Weissmann, Florian / Wu, Mary / Zeng, Jingkun

bioRxiv

Abstract: The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains ... ...

Abstract	The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains unclear, there is a need for therapeutics. Repurposing existing drugs represents a promising and potentially rapid opportunity to find novel antivirals against SARS-CoV-2. The virus encodes at least nine enzymatic activities that are potential drug targets. Here we have expressed, purified and developed enzymatic assays for SARS-CoV-2 nsp13 helicase, a viral replication protein that is essential for the coronavirus life cycle. We screened a custom chemical library of over 5000 previously characterised pharmaceuticals for nsp13 inhibitors using a FRET-based high-throughput screening (HTS) approach. From this, we have identified FPA-124 and several suramin-related compounds as novel inhibitors of nsp13 helicase activity in vitro. We describe the efficacy of these drugs using assays we developed to monitor SARS-CoV-2 growth in Vero E6 cells.
Keywords	covid19
Language	English
Publishing date	2021-04-08
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.04.07.438808
Database	COVID19

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