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Article: Insights Into Dynamics of Inhibitor and Ubiquitin-Like Protein Binding in SARS-CoV-2 Papain-Like Protease.

Bosken, Yuliana K / Cholko, Timothy / Lou, Yuan-Chao / Wu, Kuen-Phon / Chang, Chia-En A

2020 Volume 7, Page(s) 174

Abstract: Covid-19 is caused by a novel form of coronavirus for which there are currently no vaccines or anti-viral drugs. This virus, termed SARS-CoV-2 (CoV2), contains Papain-like protease (PLpro) involved in viral replication and immune response evasion. Drugs ... ...

Abstract	Covid-19 is caused by a novel form of coronavirus for which there are currently no vaccines or anti-viral drugs. This virus, termed SARS-CoV-2 (CoV2), contains Papain-like protease (PLpro) involved in viral replication and immune response evasion. Drugs targeting this protease therefore have great potential for inhibiting the virus, and have proven successful in older coronaviruses. Here, we introduce two effective inhibitors of SARS-CoV-1 (CoV1) and MERS-CoV to assess their potential for inhibiting CoV2 PLpro. We ran 1 μs molecular dynamics (MD) simulations of CoV2, CoV1, and MERS-CoV ligand-free PLpro to characterize the dynamics of CoV2 PLpro, and made comparisons between the three to elucidate important similarities and differences relevant to drug design and ubiquitin-like protein binding for deubiquitinating and deISGylating activity of CoV2. Next, we simulated the inhibitors bound to CoV1 and CoV2 PLpro in various poses and at different known binding sites to analyze their binding modes. We found that the naphthalene-based ligand shows strong potential as an inhibitor of CoV2 PLpro by binding at the putative naphthalene inhibitor binding site in both computational predictions and experimental assays. Our modeling work suggested strategies to improve naphthalene-based compounds, and our results from molecular docking showed that the newly designed compounds exhibited improved binding affinity. The other ligand, chemotherapy drug 6-mercaptopurine (6MP), showed little to no stable intermolecular interaction with PLpro and quickly dissociated or remained highly mobile. We demonstrate multiple ways to improve the binding affinity of the naphthalene-based inhibitor scaffold by engaging new residues in the unused space of the binding site. Analysis of CoV2 PLpro also brings insights into recognition of ubiquitin-like proteins that may alter innate immune response.
Keywords	covid19
Language	English
Publishing date	2020-08-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2020.00174
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Substitution of a Surface-Exposed Residue Involved in an Allosteric Network Enhances Tryptophan Synthase Function in Cells.

D'Amico, Rebecca N / Bosken, Yuliana K / O'Rourke, Kathleen F / Murray, Alec M / Admasu, Woudasie / Chang, Chia-En A / Boehr, David D

Frontiers in molecular biosciences

2021 Volume 8, Page(s) 679915

Abstract: Networks of noncovalent amino acid interactions propagate allosteric signals throughout proteins. Tryptophan synthase (TS) is an allosterically controlled bienzyme in which the indole product of the alpha subunit (αTS) is transferred through a 25 Å ... ...

Abstract	Networks of noncovalent amino acid interactions propagate allosteric signals throughout proteins. Tryptophan synthase (TS) is an allosterically controlled bienzyme in which the indole product of the alpha subunit (αTS) is transferred through a 25 Å hydrophobic tunnel to the active site of the beta subunit (βTS). Previous nuclear magnetic resonance and molecular dynamics simulations identified allosteric networks in αTS important for its function. We show here that substitution of a distant, surface-exposed network residue in αTS enhances tryptophan production, not by activating αTS function, but through dynamically controlling the opening of the indole channel and stimulating βTS activity. While stimulation is modest, the substitution also enhances cell growth in a tryptophan-auxotrophic strain of
Language	English
Publishing date	2021-05-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2021.679915
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Article ; Online: Insights Into Dynamics of Inhibitor and Ubiquitin-Like Protein Binding in SARS-CoV-2 Papain-Like Protease

Bosken, Yuliana K. / Cholko, Timothy / Lou, Yuan-Chao / Wu, Kuen-Phon / Chang, Chia-en A.

Frontiers in Molecular Biosciences

2020 Volume 7

Keywords	covid19
Publisher	Frontiers Media SA
Publishing country	ch
Document type	Article ; Online
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2020.00174
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Discovery of antimicrobial agent targeting tryptophan synthase.

Bosken, Yuliana K / Ai, Rizi / Hilario, Eduardo / Ghosh, Rittik K / Dunn, Michael F / Kan, Shih-Hsin / Niks, Dimitri / Zhou, Huanbin / Ma, Wenbo / Mueller, Leonard J / Fan, Li / Chang, Chia-En A

Protein science : a publication of the Protein Society

2021 Volume 31, Issue 2, Page(s) 432–442

Abstract: Antibiotic resistance is a continually growing challenge in the treatment of various bacterial infections worldwide. New drugs and new drug targets are necessary to curb the threat of infectious diseases caused by multidrug-resistant pathogens. The ... ...

Abstract	Antibiotic resistance is a continually growing challenge in the treatment of various bacterial infections worldwide. New drugs and new drug targets are necessary to curb the threat of infectious diseases caused by multidrug-resistant pathogens. The tryptophan biosynthesis pathway is essential for bacterial growth but is absent in higher animals and humans. Drugs that can inhibit the bacterial biosynthesis of tryptophan offer a new class of antibiotics. In this work, we combined a structure-based strategy using in silico docking screening and molecular dynamics (MD) simulations to identify compounds targeting the α subunit of tryptophan synthase with experimental methods involving the whole-cell minimum inhibitory concentration (MIC) test, solution state NMR, and crystallography to confirm the inhibition of L-tryptophan biosynthesis. Screening 1,800 compounds from the National Cancer Institute Diversity Set I against α subunit revealed 28 compounds for experimental validation; four of the 28 hit compounds showed promising activity in MIC testing. We performed solution state NMR experiments to demonstrate that a one successful inhibitor, 3-amino-3-imino-2-phenyldiazenylpropanamide (Compound 1) binds to the α subunit. We also report a crystal structure of Salmonella enterica serotype Typhimurium tryptophan synthase in complex with Compound 1 which revealed a binding site at the αβ interface of the dimeric enzyme. MD simulations were carried out to examine two binding sites for the compound. Our results show that this small molecule inhibitor could be a promising lead for future drug development.
MeSH term(s)	Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Binding Sites ; Microbial Sensitivity Tests ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Tryptophan Synthase/antagonists & inhibitors ; Tryptophan Synthase/chemistry
Chemical Substances	Anti-Bacterial Agents ; Tryptophan Synthase (EC 4.2.1.20)
Language	English
Publishing date	2021-11-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4236
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Article: Insights Into Dynamics of Inhibitor and Ubiquitin-Like Protein Binding in SARS-CoV-2 Papain-Like Protease

Bosken, Yuliana K. / Cholko, Timothy / Lou, Yuan-Chao / Wu, Kuen-Phon / Chang, Chia-En A.

Frontiers in molecular biosciences

Abstract: Covid-19 is caused by a novel form of coronavirus for which there are currently no vaccines or anti-viral drugs This virus, termed SARS-CoV-2 (CoV2), contains Papain-like protease (PLpro) involved in viral replication and immune response evasion Drugs ... ...

Abstract	Covid-19 is caused by a novel form of coronavirus for which there are currently no vaccines or anti-viral drugs This virus, termed SARS-CoV-2 (CoV2), contains Papain-like protease (PLpro) involved in viral replication and immune response evasion Drugs targeting this protease therefore have great potential for inhibiting the virus, and have proven successful in older coronaviruses Here, we introduce two effective inhibitors of SARS-CoV-1 (CoV1) and MERS-CoV to assess their potential for inhibiting CoV2 PLpro We ran 1 μs molecular dynamics (MD) simulations of CoV2, CoV1, and MERS-CoV ligand-free PLpro to characterize the dynamics of CoV2 PLpro, and made comparisons between the three to elucidate important similarities and differences relevant to drug design and ubiquitin-like protein binding for deubiquitinating and deISGylating activity of CoV2 Next, we simulated the inhibitors bound to CoV1 and CoV2 PLpro in various poses and at different known binding sites to analyze their binding modes We found that the naphthalene-based ligand shows strong potential as an inhibitor of CoV2 PLpro by binding at the putative naphthalene inhibitor binding site in both computational predictions and experimental assays Our modeling work suggested strategies to improve naphthalene-based compounds, and our results from molecular docking showed that the newly designed compounds exhibited improved binding affinity The other ligand, chemotherapy drug 6-mercaptopurine (6MP), showed little to no stable intermolecular interaction with PLpro and quickly dissociated or remained highly mobile We demonstrate multiple ways to improve the binding affinity of the naphthalene-based inhibitor scaffold by engaging new residues in the unused space of the binding site Analysis of CoV2 PLpro also brings insights into recognition of ubiquitin-like proteins that may alter innate immune response
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #732875
Database	COVID19

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Book ; Online: Table_1_Insights Into Dynamics of Inhibitor and Ubiquitin-Like Protein Binding in SARS-CoV-2 Papain-Like Protease.docx

Yuliana K. Bosken / Timothy Cholko / Yuan-Chao Lou / Kuen-Phon Wu / Chia-en A. Chang

2020

Abstract	Covid-19 is caused by a novel form of coronavirus for which there are currently no vaccines or anti-viral drugs. This virus, termed SARS-CoV-2 (CoV2), contains Papain-like protease (PLpro) involved in viral replication and immune response evasion. Drugs targeting this protease therefore have great potential for inhibiting the virus, and have proven successful in older coronaviruses. Here, we introduce two effective inhibitors of SARS-CoV-1 (CoV1) and MERS-CoV to assess their potential for inhibiting CoV2 PLpro. We ran 1 μs molecular dynamics (MD) simulations of CoV2, CoV1, and MERS-CoV ligand-free PLpro to characterize the dynamics of CoV2 PLpro, and made comparisons between the three to elucidate important similarities and differences relevant to drug design and ubiquitin-like protein binding for deubiquitinating and deISGylating activity of CoV2. Next, we simulated the inhibitors bound to CoV1 and CoV2 PLpro in various poses and at different known binding sites to analyze their binding modes. We found that the naphthalene-based ligand shows strong potential as an inhibitor of CoV2 PLpro by binding at the putative naphthalene inhibitor binding site in both computational predictions and experimental assays. Our modeling work suggested strategies to improve naphthalene-based compounds, and our results from molecular docking showed that the newly designed compounds exhibited improved binding affinity. The other ligand, chemotherapy drug 6-mercaptopurine (6MP), showed little to no stable intermolecular interaction with PLpro and quickly dissociated or remained highly mobile. We demonstrate multiple ways to improve the binding affinity of the naphthalene-based inhibitor scaffold by engaging new residues in the unused space of the binding site. Analysis of CoV2 PLpro also brings insights into recognition of ubiquitin-like proteins that may alter innate immune response.
Keywords	Biochemistry ; Molecular Biology ; Structural Biology ; Enzymes ; Protein Trafficking ; Proteomics and Intermolecular Interactions (excl. Medical Proteomics) ; Receptors and Membrane Biology ; Signal Transduction ; Structural Biology (incl. Macromolecular Modelling) ; Synthetic Biology ; structure-based drug design ; computational biology and chemistry ; non-covalent molecular recognition ; conformational change ; protein entropy ; biophysics ; protein-protein interaction ; protein inhibition ; covid19
Subject code	500 ; 570
Publishing date	2020-08-04T04:43:22Z
Publishing country	uk
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Insights Into Dynamics of Inhibitor and Ubiquitin-Like Protein Binding in SARS-CoV-2 Papain-Like Protease

Yuliana K. Bosken / Timothy Cholko / Yuan-Chao Lou / Kuen-Phon Wu / Chia-en A. Chang

Frontiers in Molecular Biosciences, Vol

2020 Volume 7

Abstract	Covid-19 is caused by a novel form of coronavirus for which there are currently no vaccines or anti-viral drugs. This virus, termed SARS-CoV-2 (CoV2), contains Papain-like protease (PLpro) involved in viral replication and immune response evasion. Drugs targeting this protease therefore have great potential for inhibiting the virus, and have proven successful in older coronaviruses. Here, we introduce two effective inhibitors of SARS-CoV-1 (CoV1) and MERS-CoV to assess their potential for inhibiting CoV2 PLpro. We ran 1 μs molecular dynamics (MD) simulations of CoV2, CoV1, and MERS-CoV ligand-free PLpro to characterize the dynamics of CoV2 PLpro, and made comparisons between the three to elucidate important similarities and differences relevant to drug design and ubiquitin-like protein binding for deubiquitinating and deISGylating activity of CoV2. Next, we simulated the inhibitors bound to CoV1 and CoV2 PLpro in various poses and at different known binding sites to analyze their binding modes. We found that the naphthalene-based ligand shows strong potential as an inhibitor of CoV2 PLpro by binding at the putative naphthalene inhibitor binding site in both computational predictions and experimental assays. Our modeling work suggested strategies to improve naphthalene-based compounds, and our results from molecular docking showed that the newly designed compounds exhibited improved binding affinity. The other ligand, chemotherapy drug 6-mercaptopurine (6MP), showed little to no stable intermolecular interaction with PLpro and quickly dissociated or remained highly mobile. We demonstrate multiple ways to improve the binding affinity of the naphthalene-based inhibitor scaffold by engaging new residues in the unused space of the binding site. Analysis of CoV2 PLpro also brings insights into recognition of ubiquitin-like proteins that may alter innate immune response.
Keywords	structure-based drug design ; computational biology and chemistry ; non-covalent molecular recognition ; conformational change ; protein entropy ; biophysics ; Biology (General) ; QH301-705.5 ; covid19
Subject code	500
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Coordinated Network Changes across the Catalytic Cycle of Alpha Tryptophan Synthase.

O'Rourke, Kathleen F / Sahu, Debashish / Bosken, Yuliana K / D'Amico, Rebecca N / Chang, Chia-En A / Boehr, David D

Structure (London, England : 1993)

2019 Volume 27, Issue 9, Page(s) 1405–1415.e5

Abstract: Networks of noncovalent interactions are important for protein structural dynamics. We used nuclear magnetic resonance chemical shift covariance analyses on an inactive variant of the alpha subunit of tryptophan synthase to map amino acid interaction ... ...

Abstract	Networks of noncovalent interactions are important for protein structural dynamics. We used nuclear magnetic resonance chemical shift covariance analyses on an inactive variant of the alpha subunit of tryptophan synthase to map amino acid interaction networks across its catalytic cycle. Although some network connections were common to every enzyme state, many of the network connections strengthened or weakened over the catalytic cycle; these changes were highly coordinated. These results suggest a higher level of network organization. Our analyses identified periodic, second-order networks that show highly coordinated interaction changes across the catalytic cycle. These periodic networks may help synchronize the sequence of structural transitions necessary for enzyme function. Molecular dynamics simulations identified interaction changes across the catalytic cycle, including those involving the catalytic residue Glu49, which may help drive other interaction changes throughout the enzyme structure. Similar periodic networks may direct structural transitions and allosteric interactions in other proteins.
MeSH term(s)	Allosteric Site ; Bacterial Proteins/chemistry ; Catalysis ; Catalytic Domain ; Models, Molecular ; Molecular Dynamics Simulation ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Conformation ; Salmonella typhimurium/enzymology ; Tryptophan Synthase/chemistry
Chemical Substances	Bacterial Proteins ; Tryptophan Synthase (EC 4.2.1.20)
Language	English
Publishing date	2019-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2019.05.013
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Article ; Online: Imaging active site chemistry and protonation states: NMR crystallography of the tryptophan synthase α-aminoacrylate intermediate.

Holmes, Jacob B / Liu, Viktoriia / Caulkins, Bethany G / Hilario, Eduardo / Ghosh, Rittik K / Drago, Victoria N / Young, Robert P / Romero, Jennifer A / Gill, Adam D / Bogie, Paul M / Paulino, Joana / Wang, Xiaoling / Riviere, Gwladys / Bosken, Yuliana K / Struppe, Jochem / Hassan, Alia / Guidoulianov, Jevgeni / Perrone, Barbara / Mentink-Vigier, Frederic /

Chang, Chia-En A / Long, Joanna R / Hooley, Richard J / Mueser, Timothy C / Dunn, Michael F / Mueller, Leonard J

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

2022 Volume 119, Issue 2

Abstract: NMR-assisted crystallography-the integrated application of solid-state NMR, X-ray crystallography, and first-principles computational chemistry-holds significant promise for mechanistic enzymology: by providing atomic-resolution characterization of ... ...

Abstract	NMR-assisted crystallography-the integrated application of solid-state NMR, X-ray crystallography, and first-principles computational chemistry-holds significant promise for mechanistic enzymology: by providing atomic-resolution characterization of stable intermediates in enzyme active sites, including hydrogen atom locations and tautomeric equilibria, NMR crystallography offers insight into both structure and chemical dynamics. Here, this integrated approach is used to characterize the tryptophan synthase α-aminoacrylate intermediate, a defining species for pyridoxal-5'-phosphate-dependent enzymes that catalyze β-elimination and replacement reactions. For this intermediate, NMR-assisted crystallography is able to identify the protonation states of the ionizable sites on the cofactor, substrate, and catalytic side chains as well as the location and orientation of crystallographic waters within the active site. Most notable is the water molecule immediately adjacent to the substrate β-carbon, which serves as a hydrogen bond donor to the ε-amino group of the acid-base catalytic residue βLys87. From this analysis, a detailed three-dimensional picture of structure and reactivity emerges, highlighting the fate of the L-serine hydroxyl leaving group and the reaction pathway back to the preceding transition state. Reaction of the α-aminoacrylate intermediate with benzimidazole, an isostere of the natural substrate indole, shows benzimidazole bound in the active site and poised for, but unable to initiate, the subsequent bond formation step. When modeled into the benzimidazole position, indole is positioned with C3 in contact with the α-aminoacrylate C
MeSH term(s)	Alanine/analogs & derivatives ; Catalysis ; Catalytic Domain ; Crystallography, X-Ray/methods ; Indoles ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy/methods ; Nuclear Magnetic Resonance, Biomolecular ; Pyridoxal Phosphate/metabolism ; Tryptophan Synthase/chemistry ; Tryptophan Synthase/metabolism
Chemical Substances	Indoles ; Pyridoxal Phosphate (5V5IOJ8338) ; indole (8724FJW4M5) ; dehydroalanine (98RA387EKY) ; Tryptophan Synthase (EC 4.2.1.20) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2022-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2109235119
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