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Article: Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms.

Rodriguez-Rivera, Frances P / Levi, Samuel M

ACS central science

2021 Volume 7, Issue 7, Page(s) 1117–1125

Abstract: Diverging from traditional target inhibition, proteasomal protein degradation approaches have emerged as novel therapeutic modalities that embody distinct pharmacological profiles and can access previously undrugged targets. Small molecule degraders have ...

Abstract	Diverging from traditional target inhibition, proteasomal protein degradation approaches have emerged as novel therapeutic modalities that embody distinct pharmacological profiles and can access previously undrugged targets. Small molecule degraders have the potential to catalytically destroy target proteins at substoichiometric concentrations, thus lowering administered doses and extending pharmacological effects. With this mechanistic premise, research efforts have advanced the development of small molecule degraders that benefit from stable and increased affinity ternary complexes. However, a holistic framework that evaluates different degradation modes from a catalytic perspective, including focusing on kinetically favored degradation mechanisms, is lacking. In this Outlook, we introduce the concept of an induced cooperativity spectrum as a unifying framework to mechanistically understand catalytic degradation profiles. This framework is bolstered by key examples of published molecular degraders extending from molecular glues to bivalent degraders. Critically, we discuss remaining challenges and future opportunities in drug discovery to rationally design and phenotypically screen for efficient degraders.
Language	English
Publishing date	2021-06-16
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2374-7943
ISSN	2374-7943
DOI	10.1021/acscentsci.1c00389
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Article ; Online: Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms

Frances P. Rodriguez-Rivera / Samuel M. Levi

ACS Central Science, Vol 7, Iss 7, Pp 1117-

2021 Volume 1125

Keywords	Chemistry ; QD1-999
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	American Chemical Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Chemically Modified Bacterial Sacculi as a Vaccine Microparticle Scaffold.

Weidenbacher, Payton A-B / Rodriguez-Rivera, Frances P / Sanyal, Mrinmoy / Visser, Joshua A / Do, Jonathan / Bertozzi, Carolyn R / Kim, Peter S

ACS chemical biology

2022 Volume 17, Issue 5, Page(s) 1184–1196

Abstract: Vaccine scaffolds and carrier proteins increase the immunogenicity of subunit vaccines. Here, we developed, characterized, and demonstrated the efficacy of a novel microparticle vaccine scaffold comprised of bacterial peptidoglycan (PGN), isolated as an ... ...

Abstract	Vaccine scaffolds and carrier proteins increase the immunogenicity of subunit vaccines. Here, we developed, characterized, and demonstrated the efficacy of a novel microparticle vaccine scaffold comprised of bacterial peptidoglycan (PGN), isolated as an entire sacculi. The PGN microparticles contain bio-orthogonal chemical handles allowing for site-specific attachment of immunogens. We first evaluated the purification, integrity, and immunogenicity of PGN microparticles derived from a variety of bacterial species. We then optimized PGN microparticle modification conditions;
MeSH term(s)	COVID-19/prevention & control ; Humans ; Peptidoglycan ; SARS-CoV-2 ; Staphylococcus aureus ; Vaccines, Conjugate ; Vaccines, Subunit
Chemical Substances	Peptidoglycan ; Vaccines, Conjugate ; Vaccines, Subunit
Language	English
Publishing date	2022-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.2c00140
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Article ; Online: μMap Photoproximity Labeling Enables Small Molecule Binding Site Mapping.

Huth, Sean W / Oakley, James V / Seath, Ciaran P / Geri, Jacob B / Trowbridge, Aaron D / Parker, Dann L / Rodriguez-Rivera, Frances P / Schwaid, Adam G / Ramil, Carlo / Ryu, Keun Ah / White, Cory H / Fadeyi, Olugbeminiyi O / Oslund, Rob C / MacMillan, David W C

Journal of the American Chemical Society

2023 Volume 145, Issue 30, Page(s) 16289–16296

Abstract: The characterization of ligand binding modes is a crucial step in the drug discovery process and is especially important in campaigns arising from phenotypic screening, where the protein target and binding mode are unknown at the outset. Elucidation of ... ...

Abstract	The characterization of ligand binding modes is a crucial step in the drug discovery process and is especially important in campaigns arising from phenotypic screening, where the protein target and binding mode are unknown at the outset. Elucidation of target binding regions is typically achieved by X-ray crystallography or photoaffinity labeling (PAL) approaches; yet, these methods present significant challenges. X-ray crystallography is a mainstay technique that has revolutionized drug discovery, but in many cases structural characterization is challenging or impossible. PAL has also enabled binding site mapping with peptide- and amino-acid-level resolution; however, the stoichiometric activation mode can lead to poor signal and coverage of the resident binding pocket. Additionally, each PAL probe can have its own fragmentation pattern, complicating the analysis by mass spectrometry. Here, we establish a robust and general photocatalytic approach toward the mapping of protein binding sites, which we define as identification of residues proximal to the ligand binding pocket. By utilizing a catalytic mode of activation, we obtain sets of labeled amino acids in the proximity of the target protein binding site. We use this methodology to map, in vitro, the binding sites of six protein targets, including several kinases and molecular glue targets, and furthermore to investigate the binding site of the STAT3 inhibitor MM-206, a ligand with no known crystal structure. Finally, we demonstrate the successful mapping of drug binding sites in live cells. These results establish μMap as a powerful method for the generation of amino-acid- and peptide-level target engagement data.
MeSH term(s)	Ligands ; Proteins/chemistry ; Binding Sites ; Peptides/chemistry ; Protein Binding
Chemical Substances	Ligands ; Proteins ; Peptides
Language	English
Publishing date	2023-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; 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.3c03325
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Article ; Online: μMap-Red: Proximity Labeling by Red Light Photocatalysis.

Buksh, Benito F / Knutson, Steve D / Oakley, James V / Bissonnette, Noah B / Oblinsky, Daniel G / Schwoerer, Michael P / Seath, Ciaran P / Geri, Jacob B / Rodriguez-Rivera, Frances P / Parker, Dann L / Scholes, Gregory D / Ploss, Alexander / MacMillan, David W C

Journal of the American Chemical Society

2022 Volume 144, Issue 14, Page(s) 6154–6162

Abstract: Modern proximity labeling techniques have enabled significant advances in understanding biomolecular interactions. However, current tools primarily utilize activation modes that are incompatible with complex biological environments, limiting our ability ... ...

Abstract	Modern proximity labeling techniques have enabled significant advances in understanding biomolecular interactions. However, current tools primarily utilize activation modes that are incompatible with complex biological environments, limiting our ability to interrogate cell- and tissue-level microenvironments in animal models. Here, we report μMap-Red, a proximity labeling platform that uses a red-light-excited Sn
MeSH term(s)	Animals ; Biotin/metabolism ; Light ; Membrane Proteins ; Mice ; Proteomics/methods ; Staining and Labeling
Chemical Substances	Membrane Proteins ; Biotin (6SO6U10H04)
Language	English
Publishing date	2022-04-01
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	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.2c01384
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Article ; Online: Acute Modulation of Mycobacterial Cell Envelope Biogenesis by Front-Line Tuberculosis Drugs.

Rodriguez-Rivera, Frances P / Zhou, Xiaoxue / Theriot, Julie A / Bertozzi, Carolyn R

Angewandte Chemie (International ed. in English)

2018 Volume 57, Issue 19, Page(s) 5267–5272

Abstract: Front-line tuberculosis (TB) drugs have been characterized extensively in vitro and in vivo with respect to gene expression and cell viability. However, little work has been devoted to understanding their effects on the physiology of the cell envelope, ... ...

Abstract	Front-line tuberculosis (TB) drugs have been characterized extensively in vitro and in vivo with respect to gene expression and cell viability. However, little work has been devoted to understanding their effects on the physiology of the cell envelope, one of the main targets of this clinical regimen. Herein, we use metabolic labeling methods to visualize the effects of TB drugs on cell envelope dynamics in mycobacterial species. We developed a new fluorophore-trehalose conjugate to visualize trehalose monomycolates of the mycomembrane using super-resolution microscopy. We also probed the relationship between mycomembrane and peptidoglycan dynamics using a dual metabolic labeling strategy. Finally, we found that metabolic labeling of both cell envelope structures reports on drug effects on cell physiology in two hours, far faster than a genetic sensor of cell envelope stress. Our work provides insight into acute drug effects on cell envelope biogenesis in live mycobacteria.
MeSH term(s)	Antitubercular Agents/pharmacology ; Cell Membrane/drug effects ; Cell Membrane/genetics ; Cell Membrane/metabolism ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis/cytology ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/metabolism ; Tuberculosis/drug therapy ; Tuberculosis/pathology
Chemical Substances	Antitubercular Agents
Language	English
Publishing date	2018-04-14
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.201712020
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Article: Visualization of mycobacterial membrane dynamics in live cells

Rodriguez-Rivera, Frances P / Bertozzi Carolyn R / Theriot Julie A / Zhou Xiaoxue

Journal of the American Chemical Society. 2017 Mar. 08, v. 139, no. 9

2017

Abstract: Mycobacteria are endowed with a highly impermeable mycomembrane that confers intrinsic resistance to many antibiotics. Several unique mycomembrane glycolipids have been isolated and structurally characterized, but the underlying organization and dynamics ...

Abstract	Mycobacteria are endowed with a highly impermeable mycomembrane that confers intrinsic resistance to many antibiotics. Several unique mycomembrane glycolipids have been isolated and structurally characterized, but the underlying organization and dynamics of glycolipids within the cell envelope remain poorly understood. We report here a study of mycomembrane dynamics that was enabled by trehaloseâfluorophore conjugates capable of labeling trehalose glycolipids in live actinomycetes. We identified fluoresceinâtrehalose analogues that are metabolically incorporated into the trehalose mycolates of representative Mycobacterium, Corynebacterium, Nocardia, and Rhodococcus species. Using these probes, we studied the mobilities of labeled glycolipids by time-lapse microscopy and fluorescence recovery after photobleaching experiments and found that mycomembrane fluidity varies widely across species and correlates with mycolic acid structure. Finally, we discovered that treatment of mycobacteria with ethambutol, a front-line tuberculosis (TB) drug, significantly increases mycomembrane fluidity. These findings enhance our understanding of mycobacterial cell envelope structure and dynamics and have implications for development of TB drug cocktails.
Keywords	antibiotics ; Corynebacterium ; drugs ; fluorescence recovery after photobleaching ; glycolipids ; microscopy ; Mycobacterium ; mycolic acids ; Nocardia ; trehalose ; tuberculosis
Language	English
Dates of publication	2017-0308
Size	p. 3488-3495.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021%2Fjacs.6b12541
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Sequential assembly of the septal cell envelope prior to V snapping in Corynebacterium glutamicum.

Zhou, Xiaoxue / Rodriguez-Rivera, Frances P / Lim, Hoong Chuin / Bell, Jason C / Bernhardt, Thomas G / Bertozzi, Carolyn R / Theriot, Julie A

Nature chemical biology

2019 Volume 15, Issue 3, Page(s) 221–231

Abstract: Members of the Corynebacterineae, including Corynebacterium and Mycobacterium, have an atypical cell envelope characterized by an additional mycomembrane outside of the peptidoglycan layer. How this multilayered cell envelope is assembled remains unclear. ...

Abstract	Members of the Corynebacterineae, including Corynebacterium and Mycobacterium, have an atypical cell envelope characterized by an additional mycomembrane outside of the peptidoglycan layer. How this multilayered cell envelope is assembled remains unclear. Here, we tracked the assembly dynamics of different envelope layers in Corynebacterium glutamicum and Mycobacterium smegmatis by using metabolic labeling and found that the septal cell envelope is assembled sequentially in both species. Additionally, we demonstrate that in C. glutamicum, the peripheral peptidoglycan layer at the septal junction remains contiguous throughout septation, forming a diffusion barrier for the fluid mycomembrane. This diffusion barrier is resolved through perforations in the peripheral peptidoglycan, thus leading to the confluency of the mycomembrane before daughter cell separation (V snapping). Furthermore, the same junctional peptidoglycan also serves as a mechanical link holding the daughter cells together and undergoes mechanical fracture during V snapping. Finally, we show that normal V snapping in C. glutamicum depends on complete assembly of the septal cell envelope.
MeSH term(s)	Bacteria ; Bacterial Outer Membrane Proteins/metabolism ; Bacterial Proteins ; Cell Division/physiology ; Cell Membrane/metabolism ; Cell Wall/metabolism ; Corynebacterium/growth & development ; Corynebacterium/metabolism ; Corynebacterium glutamicum/growth & development ; Corynebacterium glutamicum/metabolism ; Mycobacterium smegmatis/growth & development ; Mycobacterium smegmatis/metabolism ; Mycolic Acids ; Peptidoglycan
Chemical Substances	Bacterial Outer Membrane Proteins ; Bacterial Proteins ; Mycolic Acids ; Peptidoglycan
Language	English
Publishing date	2019-01-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/s41589-018-0206-1
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Article ; Online: Identification of new components of the RipC-FtsEX cell separation pathway of Corynebacterineae.

Lim, Hoong Chuin / Sher, Joel W / Rodriguez-Rivera, Frances P / Fumeaux, Coralie / Bertozzi, Carolyn R / Bernhardt, Thomas G

PLoS genetics

2019 Volume 15, Issue 8, Page(s) e1008284

Abstract: Several important human pathogens are represented in the Corynebacterineae suborder, including Mycobacterium tuberculosis and Corynebacterium diphtheriae. These bacteria are surrounded by a multilayered cell envelope composed of a cytoplasmic membrane, a ...

Abstract	Several important human pathogens are represented in the Corynebacterineae suborder, including Mycobacterium tuberculosis and Corynebacterium diphtheriae. These bacteria are surrounded by a multilayered cell envelope composed of a cytoplasmic membrane, a peptidoglycan (PG) cell wall, a second polysaccharide layer called the arabinogalactan (AG), and finally an outer membrane-like layer made of mycolic acids. Several anti-tuberculosis drugs target the biogenesis of this complex envelope, but their efficacy is declining due to resistance. New therapies are therefore needed to treat diseases caused by these organisms, and a better understanding of the mechanisms of envelope assembly should aid in their discovery. To this end, we generated the first high-density library of transposon insertion mutants in the model organism C. glutamicum. Transposon-sequencing was then used to define its essential gene set and identify loci that, when inactivated, confer hypersensitivity to ethambutol (EMB), a drug that targets AG biogenesis. Among the EMBs loci were genes encoding RipC and the FtsEX complex, a PG cleaving enzyme required for proper cell division and its predicted regulator, respectively. Inactivation of the conserved steAB genes (cgp_1603-1604) was also found to confer EMB hypersensitivity and cell division defects. A combination of quantitative microscopy, mutational analysis, and interaction studies indicate that SteA and SteB form a complex that localizes to the cytokinetic ring to promote cell separation by RipC-FtsEX and may coordinate its PG remodeling activity with the biogenesis of other envelope layers during cell division.
MeSH term(s)	Antitubercular Agents/pharmacology ; Bacterial Outer Membrane/drug effects ; Bacterial Outer Membrane/metabolism ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Biosynthetic Pathways/drug effects ; Cell Division/genetics ; Corynebacterium glutamicum/drug effects ; Corynebacterium glutamicum/physiology ; DNA Transposable Elements/genetics ; Drug Resistance, Bacterial/genetics ; Ethambutol/pharmacology ; Galactans/biosynthesis ; Genetic Loci ; Mutation ; Mycolic Acids/metabolism ; Peptidoglycan/metabolism
Chemical Substances	Antitubercular Agents ; Bacterial Proteins ; DNA Transposable Elements ; Galactans ; Mycolic Acids ; Peptidoglycan ; Ethambutol (8G167061QZ) ; arabinogalactan (SL4SX1O487)
Language	English
Publishing date	2019-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1008284
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Article ; Online: Visualization of mycobacterial membrane dynamics in live cells.

Rodriguez-Rivera, Frances P / Zhou, Xiaoxue / Theriot, Julie A / Bertozzi, Carolyn R

Journal of the American Chemical Society

2017 Volume 139, Issue 9, Page(s) 3488–3495

Abstract	Mycobacteria are endowed with a highly impermeable mycomembrane that confers intrinsic resistance to many antibiotics. Several unique mycomembrane glycolipids have been isolated and structurally characterized, but the underlying organization and dynamics of glycolipids within the cell envelope remain poorly understood. We report here a study of mycomembrane dynamics that was enabled by trehalose-fluorophore conjugates capable of labeling trehalose glycolipids in live actinomycetes. We identified fluorescein-trehalose analogues that are metabolically incorporated into the trehalose mycolates of representative Mycobacterium, Corynebacterium, Nocardia, and Rhodococcus species. Using these probes, we studied the mobilities of labeled glycolipids by time-lapse microscopy and fluorescence recovery after photobleaching experiments and found that mycomembrane fluidity varies widely across species and correlates with mycolic acid structure. Finally, we discovered that treatment of mycobacteria with ethambutol, a front-line tuberculosis (TB) drug, significantly increases mycomembrane fluidity. These findings enhance our understanding of mycobacterial cell envelope structure and dynamics and have implications for development of TB drug cocktails.
MeSH term(s)	Cell Membrane/drug effects ; Cell Membrane/metabolism ; Cell Survival ; Ethambutol/pharmacology ; Membrane Fluidity/drug effects ; Mycobacterium/cytology ; Mycobacterium/drug effects ; Thermodynamics
Chemical Substances	Ethambutol (8G167061QZ)
Language	English
Publishing date	2017-02-23
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.6b12541
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