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Article ; Online: Conformational dynamics and allosteric modulation of the SARS-CoV-2 spike.

Díaz-Salinas, Marco A / Li, Qi / Ejemel, Monir / Yurkovetskiy, Leonid / Luban, Jeremy / Shen, Kuang / Wang, Yang / Munro, James B

eLife

2022 Volume 11

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects cells through binding to angiotensin-converting enzyme 2 (ACE2). This interaction is mediated by the receptor-binding domain (RBD) of the viral spike (S) glycoprotein. Structural and ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects cells through binding to angiotensin-converting enzyme 2 (ACE2). This interaction is mediated by the receptor-binding domain (RBD) of the viral spike (S) glycoprotein. Structural and dynamic data have shown that S can adopt multiple conformations, which controls the exposure of the ACE2-binding site in the RBD. Here, using single-molecule Förster resonance energy transfer (smFRET) imaging, we report the effects of ACE2 and antibody binding on the conformational dynamics of S from the Wuhan-1 strain and in the presence of the D614G mutation. We find that D614G modulates the energetics of the RBD position in a manner similar to ACE2 binding. We also find that antibodies that target diverse epitopes, including those distal to the RBD, stabilize the RBD in a position competent for ACE2 binding. Parallel solution-based binding experiments using fluorescence correlation spectroscopy (FCS) indicate antibody-mediated enhancement of ACE2 binding. These findings inform on novel strategies for therapeutic antibody cocktails.
MeSH term(s)	Angiotensin-Converting Enzyme 2/chemistry ; COVID-19 ; Humans ; Protein Domains ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/chemistry
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	2022-03-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.75433
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: S:D614G and S:H655Y are gateway mutations that act epistatically to promote SARS-CoV-2 variant fitness.

Yurkovetskiy, Leonid / Egri, Shawn / Kurhade, Chaitanya / Diaz-Salinas, Marco A / Jaimes, Javier A / Nyalile, Thomas / Xie, Xuping / Choudhary, Manish C / Dauphin, Ann / Li, Jonathan Z / Munro, James B / Shi, Pei-Yong / Shen, Kuang / Luban, Jeremy

bioRxiv : the preprint server for biology

2023

Abstract: SARS-CoV-2 variants bearing complex combinations of mutations that confer increased transmissibility, COVID-19 severity, and immune escape, were first detected after S:D614G had gone to fixation, and likely originated during persistent infection of ... ...

Abstract	SARS-CoV-2 variants bearing complex combinations of mutations that confer increased transmissibility, COVID-19 severity, and immune escape, were first detected after S:D614G had gone to fixation, and likely originated during persistent infection of immunocompromised hosts. To test the hypothesis that S:D614G facilitated emergence of such variants, S:D614G was reverted to the ancestral sequence in the context of sequential Spike sequences from an immunocompromised individual, and within each of the major SARS-CoV-2 variants of concern. In all cases, infectivity of the S:D614G revertants was severely compromised. The infectivity of atypical SARS-CoV-2 lineages that propagated in the absence of S:D614G was found to be dependent upon either S:Q613H or S:H655Y. Notably, Gamma and Omicron variants possess both S:D614G and S:H655Y, each of which contributed to infectivity of these variants. Among sarbecoviruses, S:Q613H, S:D614G, and S:H655Y are only detected in SARS-CoV-2, which is also distinguished by a polybasic S1/S2 cleavage site. Genetic and biochemical experiments here showed that S:Q613H, S:D614G, and S:H655Y each stabilize Spike on virions, and that they are dispensable in the absence of S1/S2 cleavage, consistent with selection of these mutations by the S1/S2 cleavage site. CryoEM revealed that either S:D614G or S:H655Y shift the Spike receptor binding domain (RBD) towards the open conformation required for ACE2-binding and therefore on pathway for infection. Consistent with this, an smFRET reporter for RBD conformation showed that both S:D614G and S:H655Y spontaneously adopt the conformation that ACE2 induces in the parental Spike. Data from these orthogonal experiments demonstrate that S:D614G and S:H655Y are convergent adaptations to the polybasic S1/S2 cleavage site which stabilize S1 on the virion in the open RBD conformation and act epistatically to promote the fitness of variants bearing complex combinations of clinically significant mutations.
Language	English
Publishing date	2023-04-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.30.535005
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Article: Conformational dynamics and allosteric modulation of the SARS-CoV-2 spike.

Díaz-Salinas, Marco A / Li, Qi / Ejemel, Monir / Yurkovetskiy, Leonid / Luban, Jeremy / Shen, Kuang / Wang, Yang / Munro, James B

bioRxiv : the preprint server for biology

2021

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects cells through binding to angiotensin-converting enzyme 2 (ACE2). This interaction is mediated by the receptor-binding domain (RBD) of the viral spike (S) glycoprotein. Structural and dynamic data have shown that S can adopt multiple conformations, which controls the exposure of the ACE2-binding site in the RBD. Here, using single-molecule Förster resonance energy transfer (smFRET) imaging we report the effects of ACE2 and antibody binding on the conformational dynamics of S from the Wuhan-1 strain and the B.1 variant (D614G). We find that D614G modulates the energetics of the RBD position in a manner similar to ACE2 binding. We also find that antibodies that target diverse epitopes, including those distal to the RBD, stabilize the RBD in a position competent for ACE2 binding. Parallel solution-based binding experiments using fluorescence correlation spectroscopy (FCS) indicate antibody-mediated enhancement of ACE2 binding. These findings inform on novel strategies for therapeutic antibody cocktails.
Language	English
Publishing date	2021-11-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.10.29.466470
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Article ; Online: Conformational dynamics and allosteric modulation of the SARS-CoV-2 spike

Marco A Díaz-Salinas / Qi Li / Monir Ejemel / Leonid Yurkovetskiy / Jeremy Luban / Kuang Shen / Yang Wang / James B Munro

eLife, Vol

2022 Volume 11

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects cells through binding to angiotensin-converting enzyme 2 (ACE2). This interaction is mediated by the receptor-binding domain (RBD) of the viral spike (S) glycoprotein. Structural and dynamic data have shown that S can adopt multiple conformations, which controls the exposure of the ACE2-binding site in the RBD. Here, using single-molecule Förster resonance energy transfer (smFRET) imaging, we report the effects of ACE2 and antibody binding on the conformational dynamics of S from the Wuhan-1 strain and in the presence of the D614G mutation. We find that D614G modulates the energetics of the RBD position in a manner similar to ACE2 binding. We also find that antibodies that target diverse epitopes, including those distal to the RBD, stabilize the RBD in a position competent for ACE2 binding. Parallel solution-based binding experiments using fluorescence correlation spectroscopy (FCS) indicate antibody-mediated enhancement of ACE2 binding. These findings inform on novel strategies for therapeutic antibody cocktails.
Keywords	virus entry ; protein dynamics ; single-molecule biophysics ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Analysis of 6.4 million SARS-CoV-2 genomes identifies mutations associated with fitness.

Obermeyer, Fritz / Jankowiak, Martin / Barkas, Nikolaos / Schaffner, Stephen F / Pyle, Jesse D / Yurkovetskiy, Leonid / Bosso, Matteo / Park, Daniel J / Babadi, Mehrtash / MacInnis, Bronwyn L / Luban, Jeremy / Sabeti, Pardis C / Lemieux, Jacob E

Science (New York, N.Y.)

2022 Volume 376, Issue 6599, Page(s) 1327–1332

Abstract: Repeated emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased fitness underscores the value of rapid detection and characterization of new lineages. We have developed ... ...

Abstract	Repeated emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased fitness underscores the value of rapid detection and characterization of new lineages. We have developed PyR
MeSH term(s)	Bayes Theorem ; COVID-19/virology ; Genetic Fitness ; Genome, Viral ; Humans ; Mutation ; Regression Analysis ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abm1208
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Article ; Online: Microbiota-dependent proteolysis of gluten subverts diet-mediated protection against type 1 diabetes.

Funsten, Matthew C / Yurkovetskiy, Leonid A / Kuznetsov, Andrey / Reiman, Derek / Hansen, Camilla H F / Senter, Katharine I / Lee, Jean / Ratiu, Jeremy / Dahal-Koirala, Shiva / Antonopoulos, Dionysios A / Dunny, Gary M / Sollid, Ludvig M / Serreze, David / Khan, Aly A / Chervonsky, Alexander V

Cell host & microbe

2023 Volume 31, Issue 2, Page(s) 213–227.e9

Abstract: Diet and commensals can affect the development of autoimmune diseases like type 1 diabetes (T1D). However, whether dietary interventions are microbe-mediated was unclear. We found that a diet based on hydrolyzed casein (HC) as a protein source protects ... ...

Abstract	Diet and commensals can affect the development of autoimmune diseases like type 1 diabetes (T1D). However, whether dietary interventions are microbe-mediated was unclear. We found that a diet based on hydrolyzed casein (HC) as a protein source protects non-obese diabetic (NOD) mice in conventional and germ-free (GF) conditions via improvement in the physiology of insulin-producing cells to reduce autoimmune activation. The addition of gluten (a cereal protein complex associated with celiac disease) facilitates autoimmunity dependent on microbial proteolysis of gluten: T1D develops in GF animals monocolonized with Enterococcus faecalis harboring secreted gluten-digesting proteases but not in mice colonized with protease deficient bacteria. Gluten digestion by E. faecalis generates T cell-activating peptides and promotes innate immunity by enhancing macrophage reactivity to lipopolysaccharide (LPS). Gnotobiotic NOD Toll4-negative mice monocolonized with E. faecalis on an HC + gluten diet are resistant to T1D. These findings provide insights into strategies to develop dietary interventions to help protect humans against autoimmunity.
MeSH term(s)	Mice ; Animals ; Humans ; Diabetes Mellitus, Type 1/prevention & control ; Glutens ; Mice, Inbred NOD ; Proteolysis ; Diet ; Microbiota
Chemical Substances	Glutens (8002-80-0)
Language	English
Publishing date	2023-01-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2022.12.009
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Article ; Online: Cutting Edge: Commensal Microbiota Has Disparate Effects on Manifestations of Polyglandular Autoimmune Inflammation.

Hansen, Camilla H F / Yurkovetskiy, Leonid A / Chervonsky, Alexander V

Journal of immunology (Baltimore, Md. : 1950)

2016 Volume 197, Issue 3, Page(s) 701–705

Abstract: Polyglandular autoimmune inflammation accompanies type 1 diabetes (T1D) in NOD mice, affecting organs like thyroid and salivary glands. Although commensals are not required for T1D progression, germ-free (GF) mice had a very low degree of sialitis, which ...

Abstract	Polyglandular autoimmune inflammation accompanies type 1 diabetes (T1D) in NOD mice, affecting organs like thyroid and salivary glands. Although commensals are not required for T1D progression, germ-free (GF) mice had a very low degree of sialitis, which was restored by colonization with select microbial lineages. Moreover, unlike T1D, which is blocked in mice lacking MyD88 signaling adaptor under conventional, but not GF, housing conditions, sialitis did not develop in MyD88(-/-) GF mice. Thus, microbes and MyD88-dependent signaling are critical for sialitis development. The severity of sialitis did not correlate with the degree of insulitis in the same animal and was less sensitive to a T1D-reducing diet, but it was similar to T1D with regard to microbiota-dependent sexual dimorphism. The unexpected distinction in requirements for the microbiota for different autoimmune pathologies within the same organism is crucial for understanding the nature of microbial involvement in complex autoimmune disorders, including human autoimmune polyglandular syndromes.
MeSH term(s)	Animals ; Diabetes Mellitus, Type 1/microbiology ; Disease Models, Animal ; Female ; Germ-Free Life ; Male ; Mice ; Mice, Inbred NOD ; Mice, Knockout ; Microbiota/physiology ; Myeloid Differentiation Factor 88/immunology ; Polyendocrinopathies, Autoimmune/microbiology ; Sex Characteristics ; Sialadenitis/microbiology
Chemical Substances	Myeloid Differentiation Factor 88
Language	English
Publishing date	2016-08-01
Publishing country	United States
Document type	Journal Article
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.1502465
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Article ; Online: Microbiota and autoimmunity: exploring new avenues.

Yurkovetskiy, Leonid A / Pickard, Joseph M / Chervonsky, Alexander V

Cell host & microbe

2015 Volume 17, Issue 5, Page(s) 548–552

Abstract: Given the recognized role of the commensal microbiota in regulating host immunity to pathogens, it is not surprising that microbiota are also capable of regulating autoimmune responses. The underlying mechanisms of autoimmune regulation by the microbiota ...

Abstract	Given the recognized role of the commensal microbiota in regulating host immunity to pathogens, it is not surprising that microbiota are also capable of regulating autoimmune responses. The underlying mechanisms of autoimmune regulation by the microbiota are just beginning to emerge. Here, we discuss possible pressure points toward the development of autoimmune diseases that can be influenced by the microbiota. Besides acting on the adaptive and innate arms of the immune response, the microbiota can affect the targets of autoimmunity directly, even during development in utero, and be involved in regulation of autoimmunity via interactions with hormones.
MeSH term(s)	Adaptive Immunity ; Autoimmune Diseases/pathology ; Autoimmunity ; Immunity, Innate ; Microbiota
Language	English
Publishing date	2015-03-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2015.04.010
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Article ; Online: Deep generative models predict SARS-CoV-2 Spike infectivity and foreshadow neutralizing antibody escape

Youssef, Noor / Ghantous, Fadi / Gurev, Sarah / Brock, Kelly / Jaimes, Javier A. / Dauphin, Ann / Yurkovetskiy, Leonid / Soto, Daria / Estanboulieh, Ralph / Kotzen, Ben / Bosso, Matteo / Lemieux, Jacob / Luban, Jeremy / Seaman, Michael S. / Marks, Debora S.

bioRxiv

Abstract: Recurrent waves of SARS-CoV-2 infection, driven by the periodic emergence of new viral variants, highlight the need for vaccines and therapeutics that remain effective against future strains. Yet, our ability to proactively evaluate such therapeutics is ... ...

Abstract	Recurrent waves of SARS-CoV-2 infection, driven by the periodic emergence of new viral variants, highlight the need for vaccines and therapeutics that remain effective against future strains. Yet, our ability to proactively evaluate such therapeutics is limited to assessing their effectiveness against previous or circulating variants, which may differ significantly in their antibody escape from future viral evolution. To address this challenge, we developed deep learning methods to predict the effect of mutations on fitness and escape from neutralizing antibodies and used this information to engineer a set of 68 unique SARS-CoV-2 Spike proteins. The designed constructs, which incorporated novel combinations of up to 46 mutations relative to the ancestral strain, were infectious and evaded neutralization by nine well-characterized panels of human polyclonal anti-SARS-CoV-2 immune sera. Designed constructs on previous SARS-CoV-2 strains anticipated the antibody neutralization escape of variants seen subsequently during the COVID-19 pandemic. We demonstrate that designed Spike constructs using data available at the time of the implementation of the 2022 bivalent mRNA booster vaccine foretold the level of neutralizing antibody escape observed in the most recently emerging variants. Our approach provides extensive datasets of antigenically diverse escape variants to evaluate the protective ability of vaccines and therapeutics to inhibit future variants. This approach is generalizable to other viral pathogen
Keywords	covid19
Language	English
Publishing date	2023-10-10
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.10.08.561389
Database	COVID19

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Article ; Online: Deep generative models predict SARS-CoV-2 Spike infectivity and foreshadow neutralizing antibody escape

Youssef, Noor A / Ghantous, Fadi / Gurev, Sarah / Brock, Kelly / Jaimes, Javier A. / Dauphin, Ann / Yurkovetskiy, Leonid / Soto, Daria / Estaboulieh, Ralph / Kotzen, Ben / Bosso, Matteo / Lemieux, Jacob / Luban, Jeremy A. / Seaman, Michael / Marks, Debora

bioRxiv

Abstract	Recurrent waves of SARS-CoV-2 infection, driven by the periodic emergence of new viral variants, highlight the need for vaccines and therapeutics that remain effective against future strains. Yet, our ability to proactively evaluate such therapeutics is limited to assessing their effectiveness against previous or circulating variants, which may differ significantly in their antibody escape from future viral evolution. To address this challenge, we developed deep learning methods to predict the effect of mutations on fitness and escape from neutralizing antibodies and used this information to engineer a set of 68 unique SARS-CoV-2 Spike proteins. The designed constructs, which incorporated novel combinations of up to 46 mutations relative to the ancestral strain, were infectious and evaded neutralization by nine well-characterized panels of human polyclonal anti-SARS-CoV-2 immune sera. Designed constructs on previous SARS-CoV-2 strains anticipated the antibody neutralization escape of variants seen subsequently during the COVID-19 pandemic. We demonstrate that designed Spike constructs using data available at the time of the implementation of the 2022 bivalent mRNA booster vaccine foretold the level of neutralizing antibody escape observed in the most recently emerging variants. Our approach provides extensive datasets of antigenically diverse escape variants to evaluate the protective ability of vaccines and therapeutics to inhibit future variants. This approach is generalizable to other viral pathogen
Keywords	covid19
Language	English
Publishing date	2023-10-10
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.10.08.561389
Database	COVID19

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