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hydrogen deuterium exchange

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https://www.readbyqxmd.com/read/29355022/probing-the-conformation-of-an-igg1-monoclonal-antibody-in-lyophilized-solids-using-solid-state-hydrogen-deuterium-exchange-with-mass-spectrometric-analysis-sshdx-ms
#1
Ehab M Moussa, Satish K Singh, Michael Kimmel, Sandeep Nema, Elizabeth M Topp
Therapeutic proteins are often formulated as lyophilized products to improve their stability and prolong shelf life. The stability of proteins in the solid-state has been correlated with preservation of native higher order structure and/or molecular mobility in the solid matrix, with varying success. In the studies reported here, we used solid-state hydrogen-deuterium exchange with mass spectrometric analysis (ssHDX-MS) to study the conformation of an IgG1 monoclonal antibody (mAb) in lyophilized solids and related the extent of ssHDX to aggregation during storage in the solid phase...
January 22, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29350035/selective-proton-deuteron-transport-through-nafion-graphene-nafion-sandwich-structures-at-very-high-current-density
#2
Saheed Bukola, Ying Liang, Carol Korzeniewski, Joel Harris, Stephen Creager
Ion current densities near 1 A cm-2 at modest bias voltages (< 200 mV) are reported for proton and deuteron transmission across single-layer graphene in polyelectrolyte-membrane (PEM)-style hydrogen pump cells. The graphene is sandwiched between two Nafion membranes and covers the entire area between two platinum-carbon electrodes, such that proton transfer is forced to occur through the graphene layer. Raman spectroscopy confirms that buried graphene layers are single-layer and relatively free of defects following the hot-press procedure used to make the sandwich structures...
January 19, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29343545/tolloid-cleavage-activates-latent-gdf8-by-priming-the-pro-complex-for-dissociation
#3
Viet Q Le, Roxana E Iacob, Yuan Tian, William McConaughy, Justin Jackson, Yang Su, Bo Zhao, John R Engen, Michelle Pirruccello-Straub, Timothy A Springer
Growth differentiation factor 8 (GDF8)/myostatin is a latent TGF-β family member that potently inhibits skeletal muscle growth. Here, we compared the conformation and dynamics of precursor, latent, and Tolloid-cleaved GDF8 pro-complexes to understand structural mechanisms underlying latency and activation of GDF8. Negative stain electron microscopy (EM) of precursor and latent pro-complexes reveals a V-shaped conformation that is unaltered by furin cleavage and sharply contrasts with the ring-like, cross-armed conformation of latent TGF-β1...
January 17, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29339412/the-sequence-specific-peptide-binding-activity-of-the-protein-sulfide-isomerase-agr2-directs-its-stable-binding-to-the-oncogenic-receptor-epcam
#4
M Aiman Mohtar, Lenka Hernychova, Robert O'Neill, Melanie Lawrence, Euan Murray, Borek Vojtesek, Ted R Hupp
AGR2 is an oncogenic endoplasmic reticulum (ER)-resident protein disulfide isomerase. AGR2 protein has a relatively unique property for a chaperone in that it can bind sequence-specifically to a specific peptide motif (TTIYY). A synthetic TTIYY-containing peptide column was used to affinity-purify AGR2 from crude lysates highlighting peptide selectivity in complex mixtures. Hydrogen-deuterium exchange mass spectrometry localized the dominant region in AGR2 that interacts with the TTIYY peptide to within a structural loop from amino acids 131-135 (VDPSL)...
January 16, 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29336549/top-down-hydrogen-deuterium-exchange-analysis-of-protein-structures-using-ultraviolet-photodissociation-uvpd
#5
Nicholas I Brodie, Romain Huguet, Terry Zhang, Rosa Viner, Vlad Zabrouskov, Jingxi Pan, Evgeniy V Petrotchenko, Christoph H Borchers
Top-down hydrogen-deuterium exchange (HDX) analysis using electron capture or transfer dissociation Fourier transform mass spectrometry is a powerful method for the analysis of secondary structure of proteins in solution. The resolution of the method is a function of the extensive fragmentation of backbone bonds in the proteins. While fragmentation is usually extensive near the N- and C-termini, electron capture (ECD) or electron transfer dissociation (ETD) fragmentation methods sometimes lack good coverage of certain regions of the protein - most often in the middle of the sequence...
January 16, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29334167/cross-linking-mass-spectrometry-for-studying-protein-structures-and-protein-protein-interactions-where-are-we-now-and-where-should-we-go-from-here
#6
Andrea Sinz
Structural mass spectrometry (MS) is gaining increasing importance in deriving valuable three-dimensional structural information on proteins and protein complexes and complements existing techniques, such as NMR spectroscopy and X-ray crystallography. Structural MS unites different MS-based techniques, i.e, hydrogen-deuterium exchange, native MS, ion-mobility MS, protein footprinting, and chemical cross-linking/MS, and allows fundamental questions in structural biology to be addressed. In this article, I will focus on the cross-linking/MS strategy...
January 15, 2018: Angewandte Chemie
https://www.readbyqxmd.com/read/29331608/allosteric-effects-in-bacteriophage-hk97-procapsids-revealed-directly-from-covariance-analysis-of-cryo-em-data
#7
Nan Xu, David Veesler, Peter C Doerschuk, John E Johnson
The information content of cryo EM data sets exceeds that of the electron scattering potential (cryo EM) density initially derived for structure determination. Previously we demonstrated the power of data variance analysis for characterizing regions of cryo EM density that displayed functionally important variance anomalies associated with maturation cleavage events in Nudaurelia Omega Capensis Virus and the presence or absence of a maturation protease in bacteriophage HK97 procapsids. Here we extend the analysis in two ways...
January 10, 2018: Journal of Structural Biology
https://www.readbyqxmd.com/read/29330778/isotopic-exchange-hplc-hrms-ms-applied-to-cyclic-proanthocyanidins-in-wine-and-cranberries
#8
Edoardo Longo, Fabrizio Rossetti, Matteo Scampicchio, Emanuele Boselli
Cyclic B-type proanthocyanidins in red wines and grapes have been discovered recently. However, proanthocyanidins of a different chemical structure (non-cyclic A-type proanthocyanidins) already known to be present in cranberries and wine possess an identical theoretical mass. As a matter of fact, the retention times and the MS/MS fragmentations found for the proposed novel cyclic B-type tetrameric proanthocyanidin in red wine and the known tetrameric proanthocyanidin in a cranberry extract are herein shown to be identical...
January 12, 2018: Journal of the American Society for Mass Spectrometry
https://www.readbyqxmd.com/read/29327743/the-unexpected-racemization-and-hydrogen-deuterium-exchange-of-the-hydrogen-at-the-%C3%AE-carbon-of-proline-analogs-containing-the-5-azoniaspiro-4-4-nonyl-group
#9
B Setner, M Wierzbicka, L Jerzykiewicz, M Lisowski, Z Szewczuk
Recently, we developed a novel non-fragmenting quaternary ammonium ionization tag for the mass spectrometric sensitive sequencing of peptides, based on the N-spiro proline residue (5-azoniaspiro[4.4.]nonyl-carbonyl). Herein, we present an unexpected racemization and the hydrogen-deuterium exchange (HDX) at the α-C atom of the proline derivative under basic aqueous conditions (1% water solution of triethylamine). The deuterium atom, substituted for the α-C atom, does not undergo back-exchange under acidic aqueous conditions which makes the deuterated isotopologue a promising stabile isotope-coded internal standard for quantitative analysis by mass spectrometry...
January 12, 2018: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29326159/an-intrinsic-lipid-binding-interface-controls-sphingosine-kinase-1-function
#10
Michael J Pulkoski-Gross, Meredith L Jenkins, Jean-Philip Truman, Mohamed F Salama, Christopher J Clarke, John E Burke, Yusuf A Hannun, Lina M Obeid
Sphingosine kinase 1 (SK1) is a key enzyme which regulates a multitude of cellular processes including cellular growth, immune cell trafficking, and inflammation via the production of sphingosine-1-phosphate (S1P). To produce S1P, SK1 must access sphingosine directly from membranes. Despite the need for membrane access, the molecular mechanisms underlying SK1s direct membrane interaction remain unclear. Here, we identify a novel positively charged site on SK1 which is responsible for electrostatic interactions with membranes...
January 11, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29323490/activity-related-microsecond-dynamics-revealed-by-temperature-jump-f%C3%A3-rster-resonance-energy-transfer-measurements-on-thermophilic-alcohol-dehydrogenase
#11
Morgan B Vaughn, Jianyu Zhang, Thomas G Spiro, R Brian Dyer, Judith P Klinman
Previous studies of a thermophilic alcohol dehydrogenase (ht-ADH) demonstrated a range of discontinuous transitions at 30 °C that include catalysis, kinetic isotope effects, protein hydrogen-deuterium exchange rates, and intrinsic fluorescence properties. Using the Förster resonance energy transfer response from a Trp-NADH donor-acceptor pair in T-jump studies of ht-ADH, we now report microsecond protein motions that can be directly related to active site chemistry. Two distinctive transients are observed: a slow, kinetic process lacking a temperature break, together with a faster transient that is only detectable above 30 °C...
January 11, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29320178/novel-k-ras-g12c-switch-ii-covalent-binders-destabilize-ras-and-accelerate-nucleotide-exchange
#12
Chimno Ihuoma Nnadi, Meredith L Jenkins, Daniel R Gentile, Leslie A Bateman, Daniel Zaidman, Trent E Balius, Daniel K Nomura, John E Burke, Kevan M Shokat, Nir London
The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence of covalent drug discovery. However, covalent inhibitor design for flexible binding sites remains a difficult task due to lack of methodological development. Here, we compared covalent docking to empirical electrophile screening, against the highly dynamic target K-RasG12C. While the overall hit-rate of both methods was comparable, we were able to rapidly progress a docking hit to a potent irreversible covalent inhibitor that modifies the inactive, GDP-bound state of K-RasG12C...
January 10, 2018: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29316124/analysis-of-quaternary-structure-of-hb-beckman-variant-and-molecular-interpretation-of-its-functional-abnormality-a-mass-spectrometry-based-approach
#13
Monita Muralidharan, Rajdeep Das, Vijay Bhat, Amit Kumar Mandal
Electrostatic attraction between α and β globin chains hold the subunits together in tetrameric human hemoglobin molecule (α₂β₂). Compared to normal globin chains, the affinity of a mutant chain to its partner globin in genetic variants of hemoglobin might be different. This leads to an unequal abundance of normal and variant hemoglobin in heterozygous sample, even though the rates of synthesis of both normal and variant chains are same. The aforementioned affinities across various globin chains might be assessed by the quantification of different forms of tetramers present in a variant hemoglobin sample...
January 8, 2018: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29311508/new-gateways-to-the-platinum-group-metal-catalyzed-direct-deuterium-labeling-method-utilizing-hydrogen-as-a-catalyst-activator
#14
Yoshinari Sawama, Kwihwan Park, Tsuyoshi Yamada, Hironao Sajiki
Deuterium-labeled compounds are widely utilized in various scientific fields. We summarize the recent advances in the direct deuteration of sugar, saturated fatty acid, and arene derivatives using heterogeneous platinum group metal on carbon catalysts by our research group. Hydrogen gas is a key catalyst-activator to facilitate the present H-D exchange reactions. In this review, the direct activation method of catalysts using in situ-generated hydrogen based on the dehydrogenation of alcohols is introduced...
2018: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29299838/optimization-of-feasibility-stage-for-hydrogen-deuterium-exchange-mass-spectrometry
#15
Yoshitomo Hamuro, Stephen J Coales
The practice of HDX-MS remains somewhat difficult, not only for newcomers but also for veterans, despite its increasing popularity. While a typical HDX-MS project starts with a feasibility stage where the experimental conditions are optimized and the peptide map is generated prior to the HDX study stage, the literature usually reports only the HDX study stage. In this protocol, we describe a few considerations for the initial feasibility stage, more specifically, how to optimize quench conditions, how to tackle the carryover issue, and how to apply the pepsin specificity rule...
January 3, 2018: Journal of the American Society for Mass Spectrometry
https://www.readbyqxmd.com/read/29299701/effects-of-drying-process-on-an-igg1-monoclonal-antibody-using-solid-state-hydrogen-deuterium-exchange-with-mass-spectrometric-analysis-sshdx-ms
#16
Ehab M Moussa, Nathan E Wilson, Qi Tony Zhou, Satish K Singh, Sandeep Nema, Elizabeth M Topp
PURPOSE: Lyophilization and spray drying are widely used to manufacture solid forms of therapeutic proteins. Lyophilization is used to stabilize proteins vulnerable to degradation in solution, whereas spray drying is mainly used to prepare inhalation powders or as an alternative to freezing for storing bulk drug substance. Both processes impose stresses that may adversely affect protein structure, stability and bioactivity. Here, we compared lyophilization with and without controlled ice nucleation, and spray drying for their effects on the solid-state conformation and matrix interactions of a model IgG1 monoclonal antibody (mAb)...
January 3, 2018: Pharmaceutical Research
https://www.readbyqxmd.com/read/29287065/calmodulin-fishing-with-a-structurally-disordered-bait-triggers-cyaa-catalysis
#17
Darragh P O'Brien, Dominique Durand, Alexis Voegele, Véronique Hourdel, Marilyne Davi, Julia Chamot-Rooke, Patrice Vachette, Sébastien Brier, Daniel Ladant, Alexandre Chenal
Once translocated into the cytosol of target cells, the catalytic domain (AC) of the adenylate cyclase toxin (CyaA), a major virulence factor of Bordetella pertussis, is potently activated by binding calmodulin (CaM) to produce supraphysiological levels of cAMP, inducing cell death. Using a combination of small-angle X-ray scattering (SAXS), hydrogen/deuterium exchange mass spectrometry (HDX-MS), and synchrotron radiation circular dichroism (SR-CD), we show that, in the absence of CaM, AC exhibits significant structural disorder, and a 75-residue-long stretch within AC undergoes a disorder-to-order transition upon CaM binding...
December 29, 2017: PLoS Biology
https://www.readbyqxmd.com/read/29277478/hydrogen-deuterium-h-d-exchange-of-gelatinized-starch-studied-by-two-dimensional-2d-near-infrared-nir-correlation-spectroscopy
#18
Hideyuki Shinzawa, Junji Mizukado
Hydrogen/deuterium (H/D) exchange of gelatinized starch was probed by in-situ near-infrared (NIR) monitoring coupled with two-dimensional (2D) correlation spectroscopy. Gelatinized starch undergoes spontaneous H/D exchange in D2O. During the substitution, the exchange rate essentially becomes different depending on solvent accessibility of various parts of the molecule. Thus, by analyzing the change in the NIR feature observed during the substitution, it becomes possible to sort out local structure and dynamics of the system...
December 21, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
https://www.readbyqxmd.com/read/29258818/remodeling-of-hiv-1-nef-structure-by-src-family-kinase-binding
#19
Jamie A Moroco, John Jeff Alvarado, Ryan P Staudt, Haibin Shic, Thomas E Wales, Thomas E Smithgall, John R Engen
The HIV-1 accessory protein Nef controls multiple aspects of the viral life cycle and host immune response, making it an attractive therapeutic target. Previous X-ray crystal structures of Nef in complex with key host cell binding partners have shed light on protein-protein interactions critical to Nef function. Crystal structures of Nef in complex with either the SH3 or tandem SH3-SH2 domains of Src-family kinases reveal distinct dimer conformations of Nef. However, the existence of these Nef dimer complexes in solution has not been established...
December 16, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29248541/chicken-grifin-structural-characterization-in-crystals-and-in-solution
#20
Federico M Ruiz, Ulrich Gilles, Anna-Kristin Ludwig, Celia Sehad, Tze Chieh Shiao, Gabriel García Caballero, Herbert Kaltner, Ingo Lindner, René Roy, Dietmar Reusch, Antonio Romero, Hans-Joachim Gabius
Despite its natural abundance in lenses of vertebrates the physiological function(s) of the galectin-related inter-fiber protein (GRIFIN) is (are) still unclear. The same holds true for the significance of the unique interspecies (fish/birds vs mammals) variability in the capacity to bind lactose. In solution, ultracentrifugation and small angle X-ray scattering (at concentrations up to 9 mg/mL) characterize the protein as compact and stable homodimer without evidence for aggregation. The crystal structure of chicken (C-)GRIFIN at seven pH values from 4...
December 14, 2017: Biochimie
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