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Hydrogen-Deuterium Exchange MS

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https://www.readbyqxmd.com/read/29450991/mass-spectrometry-based-fast-photochemical-oxidation-of-proteins-fpop-for-higher-order-structure-characterization
#1
Ke Sherry Li, Liuqing Shi, Michael L Gross
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...
February 16, 2018: Accounts of Chemical Research
https://www.readbyqxmd.com/read/29436927/quantitative-analysis-of-glycation-and-its-impact-on-antigen-binding
#2
Jingjie Mo, Renzhe Jin, Qingrong Yan, Izabela Sokolowska, Michael J Lewis, Ping Hu
Glycation has been observed in antibody therapeutics manufactured by the fed-batch fermentation process. It not only increases the heterogeneity of antibodies, but also potentially affects product safety and efficacy. In this study, non-glycated and glycated fractions enriched from a monoclonal antibody (mAb1) as well as glucose-stressed mAb1 were characterized using a variety of biochemical, biophysical and biological assays to determine the effects of glycation on the structure and function of mAb1. Glycation was detected at multiple lysine residues and reduced the antigen binding activity of mAb1...
February 13, 2018: MAbs
https://www.readbyqxmd.com/read/29369433/comparing-the-fragmentation-reactions-of-protonated-cyclic-indolyl-%C3%AE-amino-esters-in-q-orbitrap-and-qtof-mass-spectrometers
#3
Xiaoji Cao, Xue Cai, Weimin Mo
RATIONALE: The comparative study of higher-energy collisional dissociation(HCD) and collision-induced dissociation(CID) mechanisms for protonated cyclic indolyl α-amino esters in quadrupole/orbitrap(Q/Orbitrap) and quadrupole time-of-flight(QTOF) mass spectrometers, respectively, is helpful to study the structures and properties of biologically active indole derivatives using tandem mass spectrometry(MS/MS) technology. METHODS: HCD and CID experiments were carried out using electrospray ionization Q/Orbitrap MS and QTOFMS in positive ion mode, respectively...
January 25, 2018: Rapid Communications in Mass Spectrometry: RCM
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
#4
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/29334167/cross-linking-mass-spectrometry-for-studying-protein-structures-and-protein-protein-interactions-where-are-we-now-and-where-should-we-go-from-here
#5
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/29330778/isotopic-exchange-hplc-hrms-ms-applied-to-cyclic-proanthocyanidins-in-wine-and-cranberries
#6
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/29299838/optimization-of-feasibility-stage-for-hydrogen-deuterium-exchange-mass-spectrometry
#7
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
#8
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
#9
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/29258818/remodeling-of-hiv-1-nef-structure-by-src-family-kinase-binding
#10
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/29239690/antibody-drug-conjugates-design-and-development-for-therapy-and-imaging-in-and-beyond-cancer-labex-mabimprove-industrial-workshop-july-27-28-2017-tours-france
#11
Camille Martin, Claire Kizlik-Masson, André Pèlegrin, Hervé Watier, Marie-Claude Viaud-Massuard, Nicolas Joubert
The annual "Antibody Industrial Symposium", co organized by LabEx MAbImprove, MabDesign and Polepharma, was held in Tours, France on June 27-28, 2017. The focus was on antibody-drug-conjugates (ADCs), new entities which realize the hope of Paul Ehrlich's magic bullet. ADCs result from the bioconjugation of a highly cytotoxic drug to a selective monoclonal antibody, which acts as a vector. Building on knowledge gained during the development of three approved ADCs, brentuximab vedotin (Adcetris®), ado trastuzumab emtansine (Kadcyla®) and inotuzumab ozogamicin (Besponsa®), and the many ADCs in development, this meeting addressed strategies and the latest innovations in the field from fundamental research to manufacturing...
December 14, 2017: MAbs
https://www.readbyqxmd.com/read/29196701/the-repeat-region-of-cortactin-is-intrinsically-disordered-in-solution
#12
Xiaofeng Li, Yeqing Tao, James W Murphy, Alexander N Scherer, TuKiet T Lam, Alan G Marshall, Anthony J Koleske, Titus J Boggon
The multi-domain protein, cortactin, contains a 37-residue repeating motif that binds to actin filaments. This cortactin repeat region comprises 6½ similar copies of the motif and binds actin filaments. To better understand this region of cortactin, and its fold, we conducted extensive biophysical analysis. Size exclusion chromatography with multi-angle light scattering (SEC-MALS) reveals that neither constructs of the cortactin repeats alone or together with the adjacent helical region homo-oligomerize. Using circular dichroism (CD) we find that in solution the cortactin repeats resemble a coil-like intrinsically disordered protein...
December 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29191828/hydrogen-deuterium-exchange-reveals-long-range-dynamical-allostery-in-soybean-lipoxygenase
#13
Adam R Offenbacher, Anthony T Iavarone, Judith P Klinman
In lipoxygenases, the topologically conserved C-terminal domain catalyzes the oxidation of polyunsaturated fatty acids, generating an assortment of biologically relevant signaling mediators. Plant and animal lipoxygenases also contain a 100-150 amino acid N-terminal C2-like domain that has been implicated in interactions with isolated fatty acids and at the phospholipid bilayer. These interactions may lead to increased substrate availability and contribute to the regulation of active site catalysis. Because of a lack of structural information, a molecular understanding of this lipid/protein interaction remains unresolved...
November 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29185984/conserved-rna-binding-specificity-of-polycomb-repressive-complex-2-is-achieved-by-dispersed-amino-acid-patches-in-ezh2
#14
Yicheng Long, Ben Bolanos, Lihu Gong, Wei Liu, Karen J Goodrich, Xin Yang, Siming Chen, Anne R Gooding, Karen A Maegley, Ketan S Gajiwala, Alexei Brooun, Thomas R Cech, Xin Liu
Polycomb repressive complex 2 (PRC2) is a key chromatin modifier responsible for methylation of lysine 27 in histone H3. PRC2 has been shown to interact with thousands of RNA species in vivo, but understanding the physiological function of RNA binding has been hampered by the lack of separation-of-function mutants. Here, we use comprehensive mutagenesis and hydrogen deuterium exchange mass spectrometry (HDX-MS) to identify critical residues for RNA interaction in PRC2 core complexes from Homo sapiens and Chaetomium thermophilum, for which crystal structures are known...
November 29, 2017: ELife
https://www.readbyqxmd.com/read/29182876/solid-state-hydrogen-deuterium-exchange-mass-spectrometry-correlation-of-deuterium-uptake-and-long-term-stability-of-lyophilized-monoclonal-antibody-formulations
#15
Balakrishnan S Moorthy, Isidro E Zarraga, Lokesh Kumar, Benjamin T Walters, Pierre Goldbach, Elizabeth M Topp, Andrea Allmendinger
Solid state hydrogen-deuterium exchange with mass spectrometric analysis (ssHDX-MS) has been used to assess protein conformation and matrix interactions in lyophilized solids. ssHDX-MS metrics have been previously correlated to the formation of aggregates of lyophilized myoglobin on storage. Here, ssHDX-MS was applied to lyophilized monoclonal antibody (mAb) formulations and correlated to their long-term stability. After exposing lyophilized samples to D2O(g), the amount of deuterium incorporated at various time points was determined by mass spectrometry for four different lyophilized mAb formulations...
November 28, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29166011/a-cooperative-folding-unit-as-the-structural-link-for-energetic-coupling-within-a-protein
#16
Nathan W Gardner, Sarah M McGinness, Jainik Panchal, Elizabeth M Topp, Chiwook Park
Previously, we demonstrated that ligand binding to Escherichia coli cofactor-dependent phosphoglycerate mutase (dPGM), a homodimeric protein, is energetically coupled with dimerization. The equilibrium unfolding of dPGM occurs with a stable, monomeric intermediate. Binding of several non-substrate metabolites stabilizes the dimeric native form over the monomeric intermediate, reducing the population of the intermediate. Both the active site and the dimer interface appear to be unfolded in the intermediate. We hypothesized that a loop containing residues 118-152 was responsible for the energetic coupling between the dimer interface and the distal active site and was unfolded in the intermediate...
November 22, 2017: Biochemistry
https://www.readbyqxmd.com/read/29151349/changes-in-enzyme-structural-dynamics-studied-by-hydrogen-exchange-mass-spectrometry-ligand-binding-effects-or-catalytically-relevant-motions
#17
Courtney S Fast, Siavash Vahidi, Lars Konermann
It is believed that enzyme catalysis is facilitated by conformational dynamics of the protein scaffold that surrounds the active site. Yet, the exact nature of catalytically relevant protein motions remains largely unknown. Hydrogen/deuterium exchange (HDX) mass spectrometry (MS) reports on backbone H-bond fluctuations. HDX/MS therefore represents a promising avenue for probing the relationship between enzyme dynamics and catalysis. A seemingly straightforward strategy for such measurements involves comparative measurements during substrate turnover and in the resting state...
November 18, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29150441/co-ii-and-ni-ii-binding-of-the-escherichia-coli-transcriptional-repressor-rcnr-orders-its-n-terminus-alters-helix-dynamics-and-reduces-dna-affinity
#18
Hsin-Ting Huang, Cedric E Bobst, Jeffrey S Iwig, Peter T Chivers, Igor A Kaltashov, Michael J Maroney
RcnR, a transcriptional regulator in Escherichia coli, derepresses the expression of the export proteins RcnAB upon binding Ni(II) or Co(II). Lack of structural information has precluded elucidation of the allosteric basis for the decreased DNA affinity in RcnR's metal-bound states. Here, using hydrogen-deuterium exchange coupled with MS (HDX-MS), we probed the RcnR structure in the presence of DNA, the cognate metal ions Ni(II) and Co(II), or the noncognate metal ion Zn(II). We found that cognate metal binding altered the flexibility from the N-terminus through helix 1 and modulated the RcnR-DNA interaction...
November 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29138428/structural-disorder-and-induced-folding-within-two-cereal-aba-stress-and-ripening-asr-proteins
#19
Karama Hamdi, Edoardo Salladini, Darragh P O'Brien, Sébastien Brier, Alexandre Chenal, Ines Yacoubi, Sonia Longhi
Abscisic acid (ABA), stress and ripening (ASR) proteins are plant-specific proteins involved in plant response to multiple abiotic stresses. We previously isolated the ASR genes and cDNAs from durum wheat (TtASR1) and barley (HvASR1). Here, we show that HvASR1 and TtASR1 are consistently predicted to be disordered and further confirm this experimentally. Addition of glycerol, which mimics dehydration, triggers a gain of structure in both proteins. Limited proteolysis showed that they are highly sensitive to protease degradation...
November 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29135326/hydrogen-deuterium-exchange-mass-spectrometry-and-computational-modeling-reveal-a-discontinuous-epitope-of-an-antibody-tl1a-interaction
#20
Richard Y-C Huang, Stanley R Krystek, Nathan Felix, Robert F Graziano, Mohan Srinivasan, Achal Pashine, Guodong Chen
TL1A, a tumor necrosis factor-like cytokine, is a ligand for the death domain receptor DR3. TL1A, upon binding to DR3, can stimulate lymphocytes and trigger secretion of proinflammatory cytokines. Therefore, blockade of TL1A/DR3 interaction may be a potential therapeutic strategy for autoimmune and inflammatory diseases. Recently, the anti-TL1A monoclonal antibody 1 (mAb1) with a strong potency in blocking the TL1A/DR3 interaction was identified. Here, we report on the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) to obtain molecular-level details of mAb1's binding epitope on TL1A...
November 14, 2017: MAbs
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