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Article ; Online: Covalent Library Screening by Targeted Mass Spectrometry for Rapid Binding Site Identification.

Nonomiya, Jim / Li, Ke Sherry / Babin, Brett M / Mulvihill, Melinda M

2023 Volume 95, Issue 7, Page(s) 3779–3788

Abstract: Interest in covalent drug discovery has surged in recent years, following the high-profile FDA approvals of covalent inhibitors that target BTK and KRAS G12C. High-throughput screening by intact protein mass spectrometry is a popular method for ... ...

Abstract	Interest in covalent drug discovery has surged in recent years, following the high-profile FDA approvals of covalent inhibitors that target BTK and KRAS G12C. High-throughput screening by intact protein mass spectrometry is a popular method for identifying lead matter from covalent fragment libraries. While the technique is proven in its capacity to confirm covalent binding, it does not provide binding site information on its own. Follow-up assays to identify binding sites can be time- and resource-intensive, potentially extending the hit confirmation timeline by weeks or months. Here, we describe the development of CoMPAS, a novel, targeted mass spectrometry-based covalent screening method that provides binding site information in the initial screen. The high sensitivity of targeted detection confers additional advantages over the intact protein method, including the ability to characterize more potent binders and reduced protein reagent requirements. Interpretation of the structure-activity relationship is simplified by enabling the use of binding site-specific EC
MeSH term(s)	Binding Sites ; High-Throughput Screening Assays ; Mass Spectrometry/methods ; Drug Discovery ; Structure-Activity Relationship ; Proteins
Chemical Substances	Proteins
Language	English
Publishing date	2023-01-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.2c04967
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Article ; Online: Covalent Library Screening by Targeted Mass Spectrometry for Rapid Binding Site Identification

Nonomiya, Jim / Li, Ke Sherry / Babin, Brett M. / Mulvihill, Melinda M.

Analytical Chemistry. 2023 Jan. 27, v. 95, no. 7 p.3779-3788

2023

Abstract	Interest in covalent drug discovery has surged in recent years, following the high-profile FDA approvals of covalent inhibitors that target BTK and KRAS G12C. High-throughput screening by intact protein mass spectrometry is a popular method for identifying lead matter from covalent fragment libraries. While the technique is proven in its capacity to confirm covalent binding, it does not provide binding site information on its own. Follow-up assays to identify binding sites can be time- and resource-intensive, potentially extending the hit confirmation timeline by weeks or months. Here, we describe the development of CoMPAS, a novel, targeted mass spectrometry-based covalent screening method that provides binding site information in the initial screen. The high sensitivity of targeted detection confers additional advantages over the intact protein method, including the ability to characterize more potent binders and reduced protein reagent requirements. Interpretation of the structure–activity relationship is simplified by enabling the use of binding site-specific EC₅₀ values. To investigate higher-throughput screening beyond what is possible with standard liquid chromatography, we acquired data in parallel on an Agilent RapidFire system and compared the screening results by statistical analysis. To demonstrate the multiplexing capabilities of CoMPAS, we determined the target selectivity of screening hits against a pool of off-target kinases.
Keywords	analytical chemistry ; drugs ; lead ; liquid chromatography ; mass spectrometry ; phosphotransferases (kinases) ; statistical analysis ; structure-activity relationships
Language	English
Dates of publication	2023-0127
Size	p. 3779-3788.
Publishing place	American Chemical Society
Document type	Article ; Online
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.2c04967
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Article ; Online: High-Throughput Kinetic Characterization of Irreversible Covalent Inhibitors of KRAS

Li, Ke Sherry / Quinn, John G / Saabye, Matthew J / Guerrero, Jesus F Salcido / Nonomiya, Jim / Lian, Qihui / Phung, Wilson / Izrayelit, Yevgeniy / Walters, Benjamin T / Gustafson, Amy / Endres, Nicholas F / Beresini, Maureen H / Mulvihill, Melinda M

Analytical chemistry

2022 Volume 94, Issue 2, Page(s) 1230–1239

Abstract: With recent advances and success in several drugs designed to treat acute and chronic diseases, targeted covalent inhibitors show a resurgence in drug discovery. As covalent inhibition is time-dependent, the preferred quantitative potency metric of ... ...

Abstract	With recent advances and success in several drugs designed to treat acute and chronic diseases, targeted covalent inhibitors show a resurgence in drug discovery. As covalent inhibition is time-dependent, the preferred quantitative potency metric of irreversible inhibitors is the second-order rate constant
MeSH term(s)	Drug Discovery ; Kinetics ; Proto-Oncogene Proteins p21(ras)
Chemical Substances	Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2022-01-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.1c04463
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Article ; Online: The

Li, Charng-Pei / Wu, Dong-Hong / Huang, Shou-Horng / Meng, Menghsiao / Shih, Hsien-Tzung / Lai, Ming-Hsin / Chen, Liang-Jwu / Jena, Kshirod K / Hechanova, Sherry Lou / Ke, Ting-Jyun / Chiu, Tai-Yuan / Tsai, Zong-Yuan / Chen, Guo-Kai / Tsai, Kuan-Chieh / Leu, Wei-Ming

International journal of molecular sciences

2023 Volume 24, Issue 2

Abstract: Brown planthopper (BPH), a monophagous phloem feeder, consumes a large amount of photoassimilates in rice and causes wilting. A near-isogenic line ‘TNG71-Bph45’ was developed from the Oryza sativa japonica variety ‘Tainung 71 (TNG71) carrying a dominant ... ...

Abstract	Brown planthopper (BPH), a monophagous phloem feeder, consumes a large amount of photoassimilates in rice and causes wilting. A near-isogenic line ‘TNG71-Bph45’ was developed from the Oryza sativa japonica variety ‘Tainung 71 (TNG71) carrying a dominant BPH-resistance locus derived from Oryza nivara (IRGC 102165) near the centromere of chromosome 4. We compared the NIL (TNG71-Bph45) and the recurrent parent to explore how the Bph45 gene confers BPH resistance. We found that TNG71-Bph45 is less attractive to BPH at least partially because it produces less limonene. Chiral analysis revealed that the major form of limonene in both rice lines was the L-form. However, both L- and D-limonene attracted BPH when applied exogenously to TNG71-Bph45 rice. The transcript amounts of limonene synthase were significantly higher in TNG71 than in TNG71-Bph45 and were induced by BPH infestation only in the former. Introgression of the Bph45 gene into another japonica variety, Tainan 11, also resulted in a low limonene content. Moreover, several dominantly acting BPH resistance genes introduced into the BPH-sensitive IR24 line compromised its limonene-producing ability and concurrently decreased its attractiveness to BPH. These observations suggest that reducing limonene production may be a common resistance strategy against BPH in rice.
MeSH term(s)	Animals ; Genes, Plant ; Hemiptera/genetics ; Limonene ; Oryza/genetics ; Plant Diseases/genetics
Chemical Substances	Limonene (9MC3I34447)
Language	English
Publishing date	2023-01-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24021798
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Article ; Online: Mass Spectrometry-Based Fast Photochemical Oxidation of Proteins (FPOP) for Higher Order Structure Characterization.

Li, Ke Sherry / Shi, Liuqing / Gross, Michael L

Accounts of chemical research

2018 Volume 51, Issue 3, Page(s) 736–744

Abstract: Assessment of protein structure and interaction is crucial for understanding protein structure/function relationships. Compared to high-resolution structural tools, including X-ray crystallography, nuclear magnetic resonance (NMR), and cryo-EM, and ... ...

Abstract	Assessment of protein structure and interaction is crucial for understanding protein structure/function relationships. Compared to high-resolution structural tools, including X-ray crystallography, nuclear magnetic resonance (NMR), and cryo-EM, and traditional low-resolution methods, such as circular dichroism, UV-vis, and florescence spectroscopy, mass spectrometry (MS)-based protein footprinting affords medium-to-high resolution (i.e., regional and residue-specific insights) by taking advantage of proteomics methods focused on the primary structure. The methodology relies on "painting" the reactive and solvent-exposed amino acid residues with chemical tags and using the pattern of modifications as footprints from analysis by bottom-up MS-based proteomics to deduce protein higher order structures. The outcome can refer to proteins in solution or even in cells and is complementary to those of X-ray crystallography and NMR. It is particularly useful in mapping protein-ligand interfaces and conformational changes resulting from ligand binding, mutation, and aggregation. Fast photochemical oxidation of proteins (FPOP), in its original conception, is a type of hydroxyl-radical-based protein footprinting that utilizes a pulsed KrF laser (248 nm) to trigger hydrolysis of hydrogen peroxide to produce solution hydroxyl radicals, which subsequently modify the protein in situ. The platform is expanding to adopt other reactive species including carbenes. The reactivity of the probe depends on the intrinsic reactivity of the radical with the residue side chain and the solvent accessibility of the residue as a function of the tertiary/quaternary structures. By introducing an appropriate scavenger to compete with hydroxyl radical self-quenching, the lifetime of the primary radicals is remarkably shortened to approximately microsecond. Thus, the sampling time scale of FPOP is much faster than hydrogen-deuterium exchange and other covalent labeling methods relying on nonradical reactions. The short footprinting time scale of FPOP offers two major advantages for protein structure elucidation: (1) it allows the protein to be interrogated in its native or near-native state with minimum structural perturbation; (2) it exhibits high sensitivity toward alterations in protein higher order structures because its sampling time is short with respect to protein conformational changes and dynamic motion. In addition, the covalent and irreversible oxidation by the hydroxyl radical provides more flexibility in the downstream proteomics workflow and MS analysis, permitting high spatial resolution with residue-specific information. Since its invention in 2005 by Hambly and Gross, FPOP has developed from proof-of-concept to a valuable biophysical tool for interrogating protein structure. In this Account, we summarize the principles and experimental design of FPOP that enable its fast labeling and describe the current and unique capabilities of the technique in protein higher order structure elucidation. Application examples include characterization of amyloid β self-assembly, protein-ligand interactions with a special emphasis on epitope mapping for protein therapeutics (e.g., antibody, Fab, and adnectin), protein folding detailed to residue-specific folding kinetics, and protein flexibility/dynamics. Additionally, the utility of FPOP-based oxidative footprinting should grow with our continuing developments of novel reagents (e.g., sulfate radical anion, carbene diradical, and trifluoromethyl radical). These reactive reagents are compatible with the current FPOP platform and offer different reactivity and selectivity toward various types of amino acid residues, providing complementary insights into protein higher order structures for soluble proteins and ultimately for membrane-bound proteins.
MeSH term(s)	Mass Spectrometry/instrumentation ; Oxidation-Reduction ; Photochemical Processes ; Protein Conformation ; Proteins/chemistry
Chemical Substances	Proteins
Language	English
Publishing date	2018-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1483291-4
ISSN	1520-4898 ; 0001-4842
ISSN (online)	1520-4898
ISSN	0001-4842
DOI	10.1021/acs.accounts.7b00593
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: High-Throughput Kinetic Characterization of Irreversible Covalent Inhibitors of KRASᴳ¹²C by Intact Protein MS and Targeted MRM

Li, Ke Sherry / Quinn, John G. / Saabye, Matthew J. / Guerrero, Jesus F. Salcido / Nonomiya, Jim / Lian, Qihui / Phung, Wilson / Izrayelit, Yevgeniy / Walters, Benjamin T. / Gustafson, Amy / Endres, Nicholas F. / Beresini, Maureen H. / Mulvihill, Melinda M.

Analytical chemistry. 2022 Jan. 06, v. 94, no. 2

2022

Abstract	With recent advances and success in several drugs designed to treat acute and chronic diseases, targeted covalent inhibitors show a resurgence in drug discovery. As covalent inhibition is time-dependent, the preferred quantitative potency metric of irreversible inhibitors is the second-order rate constant kᵢₙₐcₜ/Kᵢ, rather than IC₅₀. Here, we present the development of a mass spectrometry-based platform for rapid kinetic analysis of irreversible covalent inhibitors. Using a simple liquid handling robot for automated sample preparation and a solid-phase extraction-based RapidFire–MS system for rapid MS analysis, kinetic characterization of covalent inhibitors was performed in high throughput both by intact protein analysis and targeted multiple reaction monitoring (MRM). In addition, a bimolecular reaction model was applied to extract kᵢₙₐcₜ/Kᵢ in data fitting, providing tremendous flexibility in the experimental design to characterize covalent inhibitors with various properties. Using KRASᴳ¹²C inhibitors as a test case, the platform was demonstrated to be effective for studying covalent inhibitors with a wide range of kᵢₙₐcₜ/Kᵢ values from single digit to 3 × 10⁵ M–¹ s–¹.
Keywords	analytical chemistry ; automation ; drugs ; experimental design ; kinetics ; liquids ; mass spectrometry ; models
Language	English
Dates of publication	2022-0106
Size	p. 1230-1239.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.1c04463
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Conformational-Sensitive Fast Photochemical Oxidation of Proteins and Mass Spectrometry Characterize Amyloid Beta 1-42 Aggregation.

Li, Ke Sherry / Rempel, Don L / Gross, Michael L

Journal of the American Chemical Society

2016 Volume 138, Issue 37, Page(s) 12090–12098

Abstract: Preventing and treating Alzheimer's disease require understanding the aggregation of amyloid beta 1-42 (Aβ1-42) to give oligomers, protofibrils, and fibrils. Here we describe footprinting of Aβ1-42 by hydroxyl radical-based fast photochemical oxidation ... ...

Abstract	Preventing and treating Alzheimer's disease require understanding the aggregation of amyloid beta 1-42 (Aβ1-42) to give oligomers, protofibrils, and fibrils. Here we describe footprinting of Aβ1-42 by hydroxyl radical-based fast photochemical oxidation of proteins (FPOP) and mass spectrometry (MS) to monitor the time-course of Aβ1-42 aggregation. We resolved five distinct stages characterized by two sigmoidal behaviors, showing the time-dependent transitions of monomers-paranuclei-protofibrils-fibrillar aggregates. Kinetic modeling allows deciphering the amounts and interconversion of the dominant Aβ1-42 species. Moreover, the irreversible footprinting probe provides insights into the kinetics of oligomerization and subsequent fibrillar growth by allowing the conformational changes of Aβ1-42 at subregional and even amino-acid-residue levels to be revealed. The middle domain of Aβ1-42 plays a major role in aggregation, whereas the N-terminus retains most of its solvent-accessibility during aggregation, and the hydrophobic C-terminus is involved to an intermediate extent. This approach affords an in situ, real-time monitoring of the solvent accessibility of Aβ1-42 at various stages of oligomerization, and provides new insights on site-specific aggregation of Aβ1-42 for a sample state beyond the capabilities of most other biophysical methods.
Language	English
Publishing date	2016-09-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.6b07543
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Article ; Online: Hydrogen-Deuterium Exchange and Hydroxyl Radical Footprinting for Mapping Hydrophobic Interactions of Human Bromodomain with a Small Molecule Inhibitor.

Li, Ke Sherry / Schaper Bergman, Elizabeth T / Beno, Brett R / Huang, Richard Y-C / Deyanova, Ekaterina / Chen, Guodong / Gross, Michael L

Journal of the American Society for Mass Spectrometry

2019 Volume 30, Issue 12, Page(s) 2795–2804

Abstract: Mass spectrometry (MS)-based protein footprinting, a valuable structural tool in mapping protein-ligand interaction, has been extensively applied to protein-protein complexes, showing success in mapping large interfaces. Here, we utilized an integrated ... ...

Abstract	Mass spectrometry (MS)-based protein footprinting, a valuable structural tool in mapping protein-ligand interaction, has been extensively applied to protein-protein complexes, showing success in mapping large interfaces. Here, we utilized an integrated footprinting strategy incorporating both hydrogen-deuterium exchange (HDX) and hydroxyl radical footprinting (i.e., fast photochemical oxidation of proteins (FPOP)) for molecular-level characterization of the interaction of human bromodomain-containing protein 4 (BRD4) with a hydrophobic benzodiazepine inhibitor. HDX does not provide strong evidence for the location of the binding interface, possibly because the shielding of solvent by the small molecule is not large. Instead, HDX suggests that BRD4 appears to be stabilized by showing a modest decrease in dynamics caused by binding. In contrast, FPOP points to a critical binding region in the hydrophobic cavity, also identified by crystallography, and, therefore, exhibits higher sensitivity than HDX in mapping the interaction of BRD4 with compound 1. In the absence or under low concentrations of the radical scavenger, FPOP modifications on Met residues show significant differences that reflect the minor change in protein conformation. This problem can be avoided by using a sufficient amount of proper scavenger, as suggested by the FPOP kinetics directed by a dosimeter of the hydroxyl radical.
MeSH term(s)	Benzodiazepines/chemistry ; Benzodiazepines/pharmacology ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/metabolism ; Deuterium Exchange Measurement/methods ; Humans ; Hydrophobic and Hydrophilic Interactions ; Hydroxyl Radical/analysis ; Hydroxyl Radical/metabolism ; Models, Molecular ; Protein Conformation/drug effects ; Tandem Mass Spectrometry/methods ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/chemistry ; Transcription Factors/metabolism
Chemical Substances	BRD4 protein, human ; Cell Cycle Proteins ; Transcription Factors ; Benzodiazepines (12794-10-4) ; Hydroxyl Radical (3352-57-6)
Language	English
Publishing date	2019-11-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	1073671-2
ISSN	1879-1123 ; 1044-0305
ISSN (online)	1879-1123
ISSN	1044-0305
DOI	10.1007/s13361-019-02316-1
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Zs.A 4618: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 241: Show issues

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Article ; Online: Automated On-tip Affinity Capture Coupled with Mass Spectrometry to Characterize Intact Antibody-Drug Conjugates from Blood.

Li, Ke Sherry / Chu, Phillip Y / Fourie-O'Donohue, Aimee / Srikumar, Neha / Kozak, Katherine R / Liu, Yichin / Tran, John C

Journal of the American Society for Mass Spectrometry

2018 Volume 29, Issue 7, Page(s) 1532–1537

Abstract: Antibody-drug conjugates (ADCs) present unique challenges for ligand-binding assays primarily due to the dynamic changes of the drug-to-antibody ratio (DAR) distribution in vivo and in vitro. Here, an automated on-tip affinity capture platform with ... ...

Abstract	Antibody-drug conjugates (ADCs) present unique challenges for ligand-binding assays primarily due to the dynamic changes of the drug-to-antibody ratio (DAR) distribution in vivo and in vitro. Here, an automated on-tip affinity capture platform with subsequent mass spectrometry analysis was developed to accurately characterize the DAR distribution of ADCs from biological matrices. A variety of elution buffers were tested to offer optimal recovery, with trastuzumab serving as a surrogate to the ADCs. High assay repeatability (CV 3%) was achieved for trastuzumab antibody when captured below the maximal binding capacity of 7.5 μg. Efficient on-tip deglycosylation was also demonstrated in 1 h followed by affinity capture. Moreover, this tip-based platform affords higher throughput for DAR characterization when compared with a well-characterized bead-based method. Graphical Abstract ᅟ.
MeSH term(s)	Animals ; Antibodies, Monoclonal/blood ; Chromatography, Liquid/methods ; Haplorhini ; Humans ; Immunoconjugates/blood ; Immunoconjugates/chemistry ; Mass Spectrometry/methods ; Rats
Chemical Substances	Antibodies, Monoclonal ; Immunoconjugates
Language	English
Publishing date	2018-05-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	1073671-2
ISSN	1879-1123 ; 1044-0305
ISSN (online)	1879-1123
ISSN	1044-0305
DOI	10.1007/s13361-018-1961-7
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Zs.MO 241: Show issues

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Article: Conformational-Sensitive Fast Photochemical Oxidation of Proteins and Mass Spectrometry Characterize Amyloid Beta 1â42 Aggregation

Li, Ke Sherry / Gross Michael L / Rempel Don L

Journal of the American Chemical Society. 2016 Sept. 21, v. 138, no. 37

2016

Abstract: Preventing and treating Alzheimerâs disease require understanding the aggregation of amyloid beta 1â42 (AÎ²ââââ) to give oligomers, protofibrils, and fibrils. Here we describe footprinting of AÎ²ââââ by hydroxyl radical-based fast ... ...

Abstract	Preventing and treating Alzheimerâs disease require understanding the aggregation of amyloid beta 1â42 (AÎ²ââââ) to give oligomers, protofibrils, and fibrils. Here we describe footprinting of AÎ²ââââ by hydroxyl radical-based fast photochemical oxidation of proteins (FPOP) and mass spectrometry (MS) to monitor the time-course of AÎ²ââââ aggregation. We resolved five distinct stages characterized by two sigmoidal behaviors, showing the time-dependent transitions of monomers-paranuclei-protofibrils-fibrillar aggregates. Kinetic modeling allows deciphering the amounts and interconversion of the dominant AÎ²ââââ species. Moreover, the irreversible footprinting probe provides insights into the kinetics of oligomerization and subsequent fibrillar growth by allowing the conformational changes of AÎ²ââââ at subregional and even amino-acid-residue levels to be revealed. The middle domain of AÎ²ââââ plays a major role in aggregation, whereas the N-terminus retains most of its solvent-accessibility during aggregation, and the hydrophobic C-terminus is involved to an intermediate extent. This approach affords an in situ, real-time monitoring of the solvent accessibility of AÎ²ââââ at various stages of oligomerization, and provides new insights on site-specific aggregation of AÎ²ââââ for a sample state beyond the capabilities of most other biophysical methods.
Keywords	Alzheimer disease ; amyloid ; hydrophobicity ; mass spectrometry ; oligomerization ; oxidation
Language	English
Dates of publication	2016-0921
Size	p. 12090-12098.
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.6b07543
Database	NAL-Catalogue (AGRICOLA)

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