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Hydrogen-Deuterium Exchange MS

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https://www.readbyqxmd.com/read/28727449/the-use-of-maldi-ms-combined-with-differential-hydrogen-deuterium-exchange-for-semi-automated-protein-global-conformational-screening
#1
Gregory F Pirrone, Heather Wang, Nicole Canfield, Alexander S Chin, Timothy A Rhodes, Alexey A Makarov
Matrix-assisted laser desorption/ionization (MALDI) coupled with a time-of-flight (TOF) mass-spectrometry (MS) detector is acknowledged to be very useful for analysis of biological molecules. At the same time, hydrogen-deuterium exchange (HDX) is a well-known technique for studying protein higher-order structure. However, coupling MALDI with HDX may be challenging due to undesired back-exchange reactions during analysis. In this report, we survey an approach that utilizes MALDI coupled with automated sample preparation to compare global conformational changes of proteins under different solution conditions using differential HDX...
July 20, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28724631/the-axl-kinase-domain-in-complex-with-a-macrocyclic-inhibitor-offers-first-structural-insights-into-an-active-tam-receptor-kinase
#2
Ketan S Gajiwala, Neil Grodsky, Ben Bolaños, Junli Feng, RoseAnn Ferre, Sergei Timofeevski, Meirong Xu, Brion W Murray, Ted W Johnson, Al Stewart
The receptor tyrosine kinase (RTK) family consisting of Tyro3, Axl and Mer (TAM) is one of the most recently identified RTK families. TAM receptors are upregulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination...
July 19, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28702519/bottom-up-hydrogen-deuterium-exchange-mass-spectrometry-data-analysis-and-interpretation
#3
Kerene A Brown, Derek J Wilson
Hydrogen Deuterium Exchange (HDX) Mass Spectrometry (MS) is a sensitive analytical technique that provides information on protein conformation and dynamics in solution. It is commonly used in the study of protein-ligand and protein-protein interactions and more recently in the pharmaceutical industry for epitope mapping, screening drug candidates and in the comparison of biopharmaceuticals to biosimilars. HDX-MS monitors the exchange of protein backbone hydrogen atoms with deuterium in solution. Recent advancements in HDX automation and data analysis, have taken the emphasis off developing a fundamental understanding of HDX, which is still lacking...
July 13, 2017: Analyst
https://www.readbyqxmd.com/read/28700824/application-of-hdx-ms-to-biopharmaceutical-development-requirements-improved-sensitivity-to-detection-of-conformational-changes
#4
Lea Bonnington, Ingo Lindner, Ulrich Gilles, Tobias Kailich, Dietmar Reusch, Patrick Bulau
The usefulness of the higher-order structure information provided by hydrogen/deuterium exchange mass spectrometry (HDX-MS) in the protein therapeutic field is undisputed, however its applicability as a method for critical quality and comparability assessment has until now not been demonstrated. Here we present results demonstrating for the first time the applicability of the HDX-MS technique to monitor structural changes due to methionine oxidation at sensitivity levels realistic to the requirements of biopharmaceutical research and development...
July 12, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28657298/the-aspergillus-niger-prolyl-endoprotease-an-pep-for-hydrogen-deuterium-exchange-mass-spectrometry-and-protein-structural-studies
#5
Liana Tsiatsiani, Michiel Akeroyd, Maurien Olsthoorn, Albert J R Heck
To monitor the structural integrity of therapeutic proteins, hydrogen-deuterium exchange mass spectrometry (HDX-MS) is increasingly utilized in the pharmaceutical industry. The successful outcome of HDX-MS analyses depends on the sample preparation conditions, which involve the rapid digestion of proteins at 0°C and pH 2.5. Very few proteases are able to withstand such harsh conditions, with pepsin being the best-known exception, even though its activity is also strongly reduced at 0°C. Here, we evaluate the usage of a Prolyl-endopeptidase from Aspergillus niger (An-PEP) for HDX-MS...
June 28, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28652337/mine-conformational-dynamics-regulate-membrane-binding-mind-interaction-and-min-oscillation
#6
Kyung-Tae Park, Maria T Villar, Antonio Artigues, Joe Lutkenhaus
In Escherichia coli MinE induces MinC/MinD to oscillate between the ends of the cell, contributing to the precise placement of the Z ring at midcell. To do this, MinE undergoes a remarkable conformational change from a latent 6β-stranded form that diffuses in the cytoplasm to an active 4β-stranded form bound to the membrane and MinD. How this conformational switch occurs is not known. Here, using hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS) we rule out a model in which the two forms are in rapid equilibrium...
June 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28634122/mapping-the-binding-interface-in-a-non-covalent-size-variant-of-a-monoclonal-antibody-using-native-mass-spectrometry-hydrogen-deuterium-exchange-mass-spectrometry-and-computational-analysis
#7
Yuetian Yan, Hui Wei, Sutjano Jusuf, Stanley R Krystek, Jie Chen, Guodong Chen, Richard T Ludwig, Li Tao, Tapan K Das
Variants of monoclonal antibody containing an extra light chain has been reported in protein products(1-3). Due to potential impact on potency and immunogenicity, it is important to understand the formation mechanism of such variants so that appropriate control strategies can be implemented to assure product quality. In a model monoclonal antibody, we observed a size variant with an extra light chain non-covalently associated with the monomer (later named as "1.2mer"). The interaction between monomer and the extra light chain was characterized by native spray and hydrogen/deuterium exchange mass spectrometry (HDX MS) techniques...
June 17, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28627884/hydrogen-deuterium-exchange-mass-spectrometry-reveals-calcium-binding-properties-and-allosteric-regulation-of-downstream-regulatory-element-antagonist-modulator-dream
#8
Jun Zhang, Jing Li, Theodore A Craig, Rajiv Kumar, Michael L Gross
Downstream regulatory element antagonist modulator (DREAM) is an EF-hand Ca(2+)-binding protein that also binds to a specific DNA sequence, downstream regulatory elements (DRE), and thereby regulates transcription in a calcium-dependent fashion. DREAM binds to DRE in the absence of Ca(2+) but detaches from DRE under Ca(2+) stimulation, allowing gene expression. The Ca(2+) binding properties of DREAM and the consequences of the binding on protein structure are key to understanding the function of DREAM. Here we describe the application of hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis to investigate the Ca(2+) binding properties and the subsequent conformational changes of full-length DREAM...
July 3, 2017: Biochemistry
https://www.readbyqxmd.com/read/28621526/orthogonal-mass-spectrometry-based-footprinting-for-epitope-mapping-and-structural-characterization-the-il-6-receptor-upon-binding-of-protein-therapeutics
#9
Ke Sherry Li, Guodong Chen, Jingjie Mo, Richard Y-C Huang, Ekaterina G Deyanova, Brett R Beno, Steve R O'Neil, Adrienne A Tymiak, Michael L Gross
Higher-order structure (HOS) is a crucial determinant for the biological functions and quality attributes of protein therapeutics. Mass spectrometry (MS)-based protein footprinting approaches play an important role in elucidating the relationship between protein biophysical properties and structure. Here, we describe the use of a combined method including hydrogen-deuterium exchange (HDX), fast photochemical oxidation of proteins (FPOP), and site-specific carboxyl group footprinting to investigate the HOS of protein and protein complexes...
July 6, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28615457/deconvoluting-amp-dependent-kinase-ampk-adenine-nucleotide-binding-and-sensing
#10
Xin Gu, Yan Yan, Scott J Novick, Amanda Kovich, Devrishi Goswami, Jiyuan Ke, M H Eileen Tan, Lili Wang, Xiaodan Li, Parker de Waal, Martin R Webb, Patrick R Griffin, H Eric Xu, Karsten Melcher
AMP-activated protein kinase (AMPK) is a central cellular energy sensor that adapts metabolism and growth to the energy state of the cell. AMPK senses the ratio of adenine nucleotides (adenylate energy charge) by competitive binding of AMP, ADP, and ATP to three sites (CBS1, CBS3, and CBS4) in its γ-subunit. Since these three binding sites are functionally interconnected, it remains unclear how nucleotides bind to individual sites, which nucleotides occupy each site under physiological conditions, and how binding to one site affects binding to the other sites...
June 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28599168/impurity-profiling-of-liothyronine-sodium-by-means-of-reversed-phase-hplc-high-resolution-mass-spectrometry-on-line-h-d-exchange-and-uv-vis-absorption
#11
M Ruggenthaler, J Grass, W Schuh, C G Huber, R J Reischl
For the first time, a comprehensive investigation of the impurity profile of the synthetic thyroid API (active pharmaceutical ingredient) liothyronine sodium (LT3Na) was performed by using reversed phase HPLC and advanced structural elucidation techniques including high resolution tandem mass spectrometry (HRMS/MS) and on-line hydrogen-deuterium (H/D) exchange. Overall, 39 compounds were characterized and 25 of these related substances were previously unknown to literature. The impurity classification system recently developed for the closely related API levothyroxine sodium (LT4Na) could be applied to the newly characterized liothyronine sodium impurities resulting in a wholistic thyroid API impurity classification system...
September 5, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28596009/subzero-celsius-separations-in-three-zone-temperature-controlled-hydrogen-deuterium-exchange-mass-spectrometry
#12
Thomas E Wales, Keith E Fadgen, Michael J Eggertson, John R Engen
Hydrogen deuterium exchange mass spectrometry (HDX MS) reports on the conformational landscape of proteins by monitoring the exchange between backbone amide hydrogen atoms and deuterium in the solvent. To maintain the label for analysis, quench conditions of low temperature and pH are required during the chromatography step performed after protease digestion but before mass spectrometry. Separation at 0°C is often chosen as this is the temperature where the most deuterium can be recovered without freezing of the typical water and acetonitrile mobile phases...
June 3, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28550305/dynamics-and-ligand-induced-conformational-changes-in-human-prolyl-oligopeptidase-analyzed-by-hydrogen-deuterium-exchange-mass-spectrometry
#13
Alexandra Tsirigotaki, Roos Van Elzen, Pieter Van Der Veken, Anne-Marie Lambeir, Anastassios Economou
Prolyl oligopeptidase (PREP) is conserved in many organisms across life. It is involved in numerous processes including brain function and neuropathology, that require more than its strict proteolytic role. It consists of a seven-bladed β-propeller juxtaposed to a catalytic α/β-hydrolase domain. The conformational dynamics of PREP involved in domain motions and the gating mechanism that allows substrate accessibility remain elusive. Here we used Hydrogen Deuterium eXchange Mass Spectrometry (HDX-MS) to derive the first near-residue resolution analysis of global PREP dynamics in the presence or absence of inhibitor bound in the active site...
May 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28515318/molecular-mechanism-of-activation-of-class-ia-phosphoinositide-3-kinases-pi3ks-by-membrane-localized-hras
#14
Braden D Siempelkamp, Manoj K Rathinaswamy, Meredith L Jenkins, John E Burke
Class IA PI3Ks are involved in the generation of the key lipid signaling molecule phosphatidylinositol 3,4,5-trisphosphate (PIP3), and inappropriate activation of this pathway is implicated in a multitude of human diseases, including cancer, inflammation, and primary immunodeficiencies. Class IA PI3Ks are activated downstream of the Ras superfamily of GTPases, and Ras-PI3K interaction plays a key role in promoting tumor formation and maintenance in Ras-driven tumors. Investigating the detailed molecular events in the Ras-PI3K interaction has been challenging because it occurs on a membrane surface...
May 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28505408/ion-mobility-hydrogen-deuterium-exchange-and-isotope-scrambling-tools-to-aid-compound-identification-in-omics-mixtures
#15
Hossein Maleki, Megan M Maurer, Nima Ronaghi, Stephen J Valentine
Liquid chromatography tandem mass spectrometry (LC-MS/MS), a widely used method for comparative 'omics analysis, experiences challenges with compound identification due to matrix effects, difficulty in separating isomer and isobaric ions, and long analysis times. Ion mobility spectrometry (IMS) has proven to be useful in separating isomer and isobar ions; however, IMS-MS suffers from decreased peak capacity due to the correlation in ion size and mass. In proof-of-principle experiments, the use of gas-phase hydrogen/deuterium exchange (HDX) combined with IMS-MS/MS techniques is demonstrated to offer advantages for compound identification...
May 25, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28504253/dynamic-diversity-of-synthetic-supramolecular-polymers-in-water-as-revealed-by-hydrogen-deuterium-exchange
#16
Xianwen Lou, René P M Lafleur, Christianus M A Leenders, Sandra M C Schoenmakers, Nicholas M Matsumoto, Matthew B Baker, Joost L J van Dongen, Anja R A Palmans, E W Meijer
Numerous self-assembling molecules have been synthesized aiming at mimicking both the structural and dynamic properties found in living systems. Here we show the application of hydrogen/deuterium exchange (HDX) mass spectrometry (MS) to unravel the nanoscale organization and the structural dynamics of synthetic supramolecular polymers in water. We select benzene-1,3,5-tricarboxamide (BTA) derivatives that self-assemble in H2O to illustrate the strength of this technique for supramolecular polymers. The BTA structure has six exchangeable hydrogen atoms and we follow their exchange as a function of time after diluting the H2O solution with a 100-fold excess of D2O...
May 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28497950/deamidation-slows-curli-amyloid-protein-aggregation
#17
COMPARATIVE STUDY
Hanliu Wang, Qin Shu, Carl Frieden, Michael L Gross
Nonenzymatic deamidation of asparagine and glutamine in peptides and proteins is a frequent modification both in vivo and in vitro. The biological effect is not completely understood, but it is often associated with protein degradation and loss of biological function. Here we describe the deamidation of CsgA, the major protein subunit of curli, which are important proteinaceous components of biofilms. CsgA has a high content of Asn and Gln, a feature seen in a few proteins that self-aggregate. We have implemented an approach to monitor deamidation rapidly by following the globally centroid mass shift, providing guidance for studies at the residue level...
June 13, 2017: Biochemistry
https://www.readbyqxmd.com/read/28488200/application-of-atmospheric-pressure-photoionization-h-d-exchange-mass-spectrometry-for-speciation-of-sulfur-containing-compounds
#18
Thamina Acter, Donghwi Kim, Arif Ahmed, Ji-Hyoung Ha, Sunghwan Kim
Herein we report the observation of atmospheric pressure in-source hydrogen-deuterium exchange (HDX) of thiol group for the first time. The HDX for thiol group was optimized for positive atmospheric pressure photoionization (APPI) mass spectrometry (MS). The optimized HDX-MS was applied for 31 model compounds (thiols, thiophenes, and sulfides) to demonstrate that exchanged peaks were observed only for thiols. The optimized method has been successfully applied to the isolated fractions of sulfur-rich oil samples...
August 2017: Journal of the American Society for Mass Spectrometry
https://www.readbyqxmd.com/read/28481113/hydrogen-deuterium-exchange-mass-spectrometry-reveals-mechanistic-details-of-activation-of-nucleoside-diphosphate-kinases-by-oligomerization
#19
COMPARATIVE STUDY
Alain Dautant, Philippe Meyer, Florian Georgescauld
Most oligomeric proteins become active only after assembly, but why oligomerization is required to support function is not well understood. Here, we address this question using the wild type (WT) and a destabilized mutant (D93N) of the hexameric nucleoside diphosphate kinase from the pathogen Mycobacterium tuberculosis (Mt-NDPK). The conformational dynamics and oligomeric states of each were analyzed during unfolding and/or folding by hydrogen/deuterium exchange mass spectrometry (HDX-MS) at peptide resolution and by additional biochemical techniques...
June 13, 2017: Biochemistry
https://www.readbyqxmd.com/read/28474266/gas-phase-intercluster-thiyl-radical-induced-c-h-bond-homolysis-selectively-forms-sugar-c2-radical-cations-of-methyl-d-glucopyranoside-isotopic-labeling-studies-and-cleavage-reactions
#20
Sandra Osburn, Gaetano Speciale, Spencer J Williams, Richard A J O'Hair
A suite of isotopologues of methyl D-glucopyranosides is used in conjunction with multistage mass spectrometry experiments to determine the radical site and cleavage reactions of sugar radical cations formed via a recently developed 'bio-inspired' method. In the first stage of CID (MS(2)), collision-induced dissociation (CID) of a protonated noncovalent complex between the sugar and S-nitrosocysteamine, [H3NCH2CH2SNO + M](+), unleashes a thiyl radical via bond homolysis to give the noncovalent radical cation, [H3NCH2CH2S(•) + M](+)...
May 4, 2017: Journal of the American Society for Mass Spectrometry
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