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Article ; Online: Oligomeric Remodeling by Molecular Glues Revealed Using Native Mass Spectrometry and Mass Photometry.

Huang, Xiaojing / Kamadurai, Hari / Siuti, Piro / Ahmed, Ezaz / Bennett, Jack L / Donald, William A

Journal of the American Chemical Society

2023 Volume 145, Issue 27, Page(s) 14716–14726

Abstract: Molecular glues stabilize interactions between E3 ligases and novel substrates to promote substrate degradation, thereby facilitating the inhibition of traditionally "undruggable" protein targets. However, most known molecular glues have been discovered ... ...

Abstract	Molecular glues stabilize interactions between E3 ligases and novel substrates to promote substrate degradation, thereby facilitating the inhibition of traditionally "undruggable" protein targets. However, most known molecular glues have been discovered fortuitously or are based on well-established chemical scaffolds. Efficient approaches for discovering and characterizing the effects of molecular glues on protein interactions are required to accelerate the discovery of novel agents. Here, we demonstrate that native mass spectrometry and mass photometry can provide unique insights into the physical mechanism of molecular glues, revealing previously unknown effects of such small molecules on the oligomeric organization of E3 ligases. When compared to well-established solution phase assays, native mass spectrometry provides accurate quantitative descriptions of molecular glue potency and efficacy while also enabling the binding specificity of E3 ligases to be determined in a single, rapid measurement. Such mechanistic insights should accelerate the rational development of molecular glues to afford powerful therapeutic agents.
MeSH term(s)	Ubiquitin-Protein Ligases/metabolism ; Mass Spectrometry ; Photometry ; Proteolysis
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Journal Article ; 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.3c02655
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Protein-Small Molecule Interactions in Native Mass Spectrometry.

Bennett, Jack L / Nguyen, Giang T H / Donald, William A

Chemical reviews

2021 Volume 122, Issue 8, Page(s) 7327–7385

Abstract: Small molecule drug discovery has been propelled by the continual development of novel scientific methodologies to occasion therapeutic advances. Although established biophysical methods can be used to obtain information regarding the molecular ... ...

Abstract	Small molecule drug discovery has been propelled by the continual development of novel scientific methodologies to occasion therapeutic advances. Although established biophysical methods can be used to obtain information regarding the molecular mechanisms underlying drug action, these approaches are often inefficient, low throughput, and ineffective in the analysis of heterogeneous systems including dynamic oligomeric assemblies and proteins that have undergone extensive post-translational modification. Native mass spectrometry can be used to probe protein-small molecule interactions with unprecedented speed and sensitivity, providing unique insights into polydisperse biomolecular systems that are commonly encountered during the drug discovery process. In this review, we describe potential and proven applications of native MS in the study of interactions between small, drug-like molecules and proteins, including large multiprotein complexes and membrane proteins. Approaches to quantify the thermodynamic and kinetic properties of ligand binding are discussed, alongside a summary of gas-phase ion activation techniques that have been used to interrogate the structure of protein-small molecule complexes. We additionally highlight some of the key areas in modern drug design for which native mass spectrometry has elicited significant advances. Future developments and applications of native mass spectrometry in drug discovery workflows are identified, including potential pathways toward studying protein-small molecule interactions on a whole-proteome scale.
MeSH term(s)	Drug Discovery/methods ; Mass Spectrometry/methods ; Membrane Proteins ; Proteome ; Thermodynamics
Chemical Substances	Membrane Proteins ; Proteome
Language	English
Publishing date	2021-08-27
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	207949-5
ISSN	1520-6890 ; 0009-2665
ISSN (online)	1520-6890
ISSN	0009-2665
DOI	10.1021/acs.chemrev.1c00293
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Article ; Online: Binding of Per- and Polyfluoroalkyl Substances to β-Lactoglobulin from Bovine Milk.

Pham, P Chi / Taylor, Mackenzie / Nguyen, Giang T H / Beltran, Jeunesse / Bennett, Jack L / Ho, Junming / Donald, William A

Chemical research in toxicology

2024

Abstract: Per- and polyfluoroalkyl substances (PFAS) are known for their high environmental persistence and potential toxicity. The presence of PFAS has been reported in many dairy products. However, the mechanisms underlying the accumulation of PFAS in these ... ...

Abstract	Per- and polyfluoroalkyl substances (PFAS) are known for their high environmental persistence and potential toxicity. The presence of PFAS has been reported in many dairy products. However, the mechanisms underlying the accumulation of PFAS in these products remain unclear. Here, we used native mass spectrometry and molecular dynamics simulations to probe the interactions between 19 PFAS of environmental concern and two isoforms of the major bovine whey protein β-lactoglobulin (β-LG). We observed that six of these PFAS bound to both protein isoforms with low- to mid-micromolar dissociation constants. Based on quantitative, competitive binding experiments with endogenous ligands, PFAS can bind orthosterically and preferentially to β-LG's hydrophobic ligand-binding calyx. β-Cyclodextrin can also suppress binding of PFAS to β-LG owing to the ability of β-cyclodextrin to directly sequester PFAS from solution. This research sheds light on PFAS-β-LG binding, suggesting that such interactions could impact lipid-fatty acid transport in bovine mammary glands at high PFAS concentrations. Furthermore, our results highlight the potential use of β-cyclodextrin in mitigating PFAS binding, providing insights toward the development of strategies to reduce PFAS accumulation in dairy products and other biological systems.
Language	English
Publishing date	2024-04-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.4c00021
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Article ; Online: Phospholipids Differentially Regulate Ca

Lawrence, Sophie A S / Kirschbaum, Carla / Bennett, Jack L / Lutomski, Corinne A / El-Baba, Tarick J / Robinson, Carol V

ACS chemical biology

2024 Volume 19, Issue 4, Page(s) 953–961

Abstract: Synaptotagmin-1 (Syt-1) is a calcium sensing protein that is resident in synaptic vesicles. It is well established that Syt-1 is essential for fast and synchronous neurotransmitter release. However, the role of ... ...

Abstract	Synaptotagmin-1 (Syt-1) is a calcium sensing protein that is resident in synaptic vesicles. It is well established that Syt-1 is essential for fast and synchronous neurotransmitter release. However, the role of Ca
MeSH term(s)	Calcium/metabolism ; Exocytosis/physiology ; Neurotransmitter Agents/metabolism ; Phospholipids/metabolism ; Synaptic Transmission/physiology ; Synaptic Vesicles/metabolism ; Synaptotagmin I/metabolism ; Animals ; Rats
Chemical Substances	Calcium (SY7Q814VUP) ; Neurotransmitter Agents ; Phospholipids ; Synaptotagmin I ; 1,2-dioleoylphosphatidylserine (70614-14-1)
Language	English
Publishing date	2024-04-02
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.3c00772
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Protein–Small Molecule Interactions in Native Mass Spectrometry

Bennett, Jack L. / Nguyen, Giang T. H. / Donald, William A.

Chemical reviews. 2021 Aug. 27, v. 122, no. 8

2021

Abstract	Small molecule drug discovery has been propelled by the continual development of novel scientific methodologies to occasion therapeutic advances. Although established biophysical methods can be used to obtain information regarding the molecular mechanisms underlying drug action, these approaches are often inefficient, low throughput, and ineffective in the analysis of heterogeneous systems including dynamic oligomeric assemblies and proteins that have undergone extensive post-translational modification. Native mass spectrometry can be used to probe protein–small molecule interactions with unprecedented speed and sensitivity, providing unique insights into polydisperse biomolecular systems that are commonly encountered during the drug discovery process. In this review, we describe potential and proven applications of native MS in the study of interactions between small, drug-like molecules and proteins, including large multiprotein complexes and membrane proteins. Approaches to quantify the thermodynamic and kinetic properties of ligand binding are discussed, alongside a summary of gas-phase ion activation techniques that have been used to interrogate the structure of protein–small molecule complexes. We additionally highlight some of the key areas in modern drug design for which native mass spectrometry has elicited significant advances. Future developments and applications of native mass spectrometry in drug discovery workflows are identified, including potential pathways toward studying protein–small molecule interactions on a whole-proteome scale.
Keywords	drug design ; drugs ; ligands ; mass spectrometry ; post-translational modification ; therapeutics ; thermodynamics
Language	English
Dates of publication	2021-0827
Size	p. 7327-7385.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	207949-5
ISSN	1520-6890 ; 0009-2665
ISSN (online)	1520-6890
ISSN	0009-2665
DOI	10.1021/acs.chemrev.1c00293
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Multiplexed Screening of Thousands of Natural Products for Protein-Ligand Binding in Native Mass Spectrometry.

Nguyen, Giang T H / Bennett, Jack L / Liu, Sherrie / Hancock, Sarah E / Winter, Daniel L / Glover, Dominic J / Donald, William A

Journal of the American Chemical Society

2021 Volume 143, Issue 50, Page(s) 21379–21387

Abstract: The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we ... ...

Abstract	The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we introduce a mass spectrometry-based approach that integrates untargeted metabolomics with multistage, high-resolution native mass spectrometry to rapidly identify natural products that bind to therapeutically relevant protein targets. By directly screening crude natural product extracts containing thousands of drug-like small molecules using a single, rapid measurement, we could identify novel natural product ligands of human drug targets without fractionation. This method should significantly increase the efficiency of target-based natural product drug discovery workflows.
MeSH term(s)	Biological Products/chemistry ; Biological Products/metabolism ; Carbonic Anhydrase I/chemistry ; Carbonic Anhydrase I/metabolism ; Chromatography, High Pressure Liquid ; Humans ; Ligands ; Metabolomics/methods ; Proteins/chemistry ; Proteins/metabolism ; Tandem Mass Spectrometry
Chemical Substances	Biological Products ; Ligands ; Proteins ; Carbonic Anhydrase I (EC 4.2.1.-)
Language	English
Publishing date	2021-12-10
Publishing country	United States
Document type	Journal Article ; 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.1c10408
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Multiplexed Screening of Thousands of Natural Products for Protein–Ligand Binding in Native Mass Spectrometry

Nguyen, Giang T. H. / Bennett, Jack L. / Liu, Sherrie / Hancock, Sarah E. / Winter, Daniel L. / Glover, Dominic J. / Donald, William A.

Journal of the American Chemical Society. 2021 Dec. 10, v. 143, no. 50

2021

Abstract	The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we introduce a mass spectrometry-based approach that integrates untargeted metabolomics with multistage, high-resolution native mass spectrometry to rapidly identify natural products that bind to therapeutically relevant protein targets. By directly screening crude natural product extracts containing thousands of drug-like small molecules using a single, rapid measurement, we could identify novel natural product ligands of human drug targets without fractionation. This method should significantly increase the efficiency of target-based natural product drug discovery workflows.
Keywords	drugs ; fractionation ; humans ; ligands ; mass spectrometry ; metabolomics
Language	English
Dates of publication	2021-1210
Size	p. 21379-21387.
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/jacs.1c10408
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Infrared Multiphoton Dissociation Enables Top-Down Characterization of Membrane Protein Complexes and G Protein-Coupled Receptors.

Lutomski, Corinne A / El-Baba, Tarick J / Hinkle, Joshua D / Liko, Idlir / Bennett, Jack L / Kalmankar, Neha V / Dolan, Andrew / Kirschbaum, Carla / Greis, Kim / Urner, Leonhard H / Kapoor, Parth / Yen, Hsin-Yung / Pagel, Kevin / Mullen, Christopher / Syka, John E P / Robinson, Carol V

Angewandte Chemie (International ed. in English)

2023 Volume 62, Issue 36, Page(s) e202305694

Abstract: Membrane proteins are challenging to analyze by native mass spectrometry (MS) as their hydrophobic nature typically requires stabilization in detergent micelles that are removed prior to analysis via collisional activation. There is however a practical ... ...

Abstract	Membrane proteins are challenging to analyze by native mass spectrometry (MS) as their hydrophobic nature typically requires stabilization in detergent micelles that are removed prior to analysis via collisional activation. There is however a practical limit to the amount of energy which can be applied, which often precludes subsequent characterization by top-down MS. To overcome this barrier, we have applied a modified Orbitrap Eclipse Tribrid mass spectrometer coupled to an infrared laser within a high-pressure linear ion trap. We show how tuning the intensity and time of incident photons enables liberation of membrane proteins from detergent micelles. Specifically, we relate the ease of micelle removal to the infrared absorption of detergents in both condensed and gas phases. Top-down MS via infrared multiphoton dissociation (IRMPD), results in good sequence coverage enabling unambiguous identification of membrane proteins and their complexes. By contrasting and comparing the fragmentation patterns of the ammonia channel with two class A GPCRs, we identify successive cleavage of adjacent amino acids within transmembrane domains. Using gas-phase molecular dynamics simulations, we show that areas prone to fragmentation maintain aspects of protein structure at increasing temperatures. Altogether, we propose a rationale to explain why and where in the protein fragment ions are generated.
MeSH term(s)	Detergents ; Micelles ; Mass Spectrometry/methods ; Membrane Proteins ; Receptors, G-Protein-Coupled
Chemical Substances	Detergents ; Micelles ; Membrane Proteins ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2023-07-25
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202305694
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Infrared Multiphoton Dissociation Enables Top-Down Characterization of Membrane Protein Complexes and G Protein-Coupled Receptors.

Angewandte Chemie (Weinheim an der Bergstrasse, Germany)

2023 Volume 135, Issue 36, Page(s) e202305694

Abstract	Membrane proteins are challenging to analyze by native mass spectrometry (MS) as their hydrophobic nature typically requires stabilization in detergent micelles that are removed prior to analysis via collisional activation. There is however a practical limit to the amount of energy which can be applied, which often precludes subsequent characterization by top-down MS. To overcome this barrier, we have applied a modified Orbitrap Eclipse Tribrid mass spectrometer coupled to an infrared laser within a high-pressure linear ion trap. We show how tuning the intensity and time of incident photons enables liberation of membrane proteins from detergent micelles. Specifically, we relate the ease of micelle removal to the infrared absorption of detergents in both condensed and gas phases. Top-down MS via infrared multiphoton dissociation (IRMPD), results in good sequence coverage enabling unambiguous identification of membrane proteins and their complexes. By contrasting and comparing the fragmentation patterns of the ammonia channel with two class A GPCRs, we identify successive cleavage of adjacent amino acids within transmembrane domains. Using gas-phase molecular dynamics simulations, we show that areas prone to fragmentation maintain aspects of protein structure at increasing temperatures. Altogether, we propose a rationale to explain why and where in the protein fragment ions are generated.
Language	English
Publishing date	2023-07-25
Publishing country	Germany
Document type	Journal Article
ZDB-ID	506609-8
ISSN	1521-3757 ; 0044-8249 ; 0932-2140
ISSN (online)	1521-3757
ISSN	0044-8249 ; 0932-2140
DOI	10.1002/ange.202305694
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Article ; Online: Delivering bioactive cyclic peptides that target Hsp90 as prodrugs.

Huo, Yuantao / Buckton, Laura K / Bennett, Jack L / Smith, Eloise C / Byrne, Frances L / Hoehn, Kyle L / Rahimi, Marwa N / McAlpine, Shelli R

Journal of enzyme inhibition and medicinal chemistry

2019 Volume 34, Issue 1, Page(s) 728–739

Abstract: The most challenging issue facing peptide drug development is producing a molecule with optimal physical properties while maintaining target binding affinity. Masking peptides with protecting groups that can be removed inside the cell, produces a cell- ... ...

Abstract	The most challenging issue facing peptide drug development is producing a molecule with optimal physical properties while maintaining target binding affinity. Masking peptides with protecting groups that can be removed inside the cell, produces a cell-permeable peptide, which theoretically can maintain its biological activity. Described are series of prodrugs masked using: (a) O-alkyl, (b) N-alkyl, and (c) acetyl groups, and their binding affinity for Hsp90. Alkyl moieties increased compound permeability, P
MeSH term(s)	Animals ; Dose-Response Relationship, Drug ; HSP90 Heat-Shock Proteins/antagonists & inhibitors ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Mice ; Microsomes, Liver/chemistry ; Microsomes, Liver/metabolism ; Molecular Structure ; Peptides, Cyclic/chemistry ; Peptides, Cyclic/metabolism ; Peptides, Cyclic/pharmacology ; Prodrugs/chemistry ; Prodrugs/metabolism ; Prodrugs/pharmacology ; Structure-Activity Relationship
Chemical Substances	HSP90 Heat-Shock Proteins ; Peptides, Cyclic ; Prodrugs
Language	English
Publishing date	2019-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2082578-X
ISSN	1475-6374 ; 1475-6366
ISSN (online)	1475-6374
ISSN	1475-6366
DOI	10.1080/14756366.2019.1580276
Database	MEDical Literature Analysis and Retrieval System OnLINE

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