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Hydrogen-Deuterium Exchange MS

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https://www.readbyqxmd.com/read/27924262/mass-spectrometric-analysis-of-protein-ligand-interactions
#1
Kentaro Ishii, Masanori Noda, Susumu Uchiyama
The interactions of small molecules with proteins (protein-ligand interactions) mediate various biological phenomena including signal transduction and protein transcription and translation. Synthetic compounds such as drugs can also bind to target proteins, leading to the inhibition of protein-ligand interactions. These interactions typically accompany association-dissociation equilibrium according to the free energy difference between free and bound states; therefore, the quantitative biophysical analysis of the interactions, which uncovers the stoichiometry and dissociation constant, is important for understanding biological reactions as well as for rational drug development...
2016: Biophysics and Physicobiology
https://www.readbyqxmd.com/read/27916388/application-of-dual-protease-column-for-hdx-ms-analysis-of-monoclonal-antibodies
#2
Sasidhar N Nirudodhi, Justin B Sperry, Jason C Rouse, James A Carroll
A co-immobilized, dual protease column was developed and implemented to more efficiently digest IgG molecules for hydrogen/deuterium exchange mass spectrometry (HDX-MS). The low-pH proteolytic enzymes pepsin and type XIII protease from Aspergillus were packed into a single column to most effectively combine the complementary specificities. The method was optimized using an IgG2 monoclonal antibody as a substrate because they are known to be more difficult to efficiently digest. The general applicability of the method was then demonstrated using IgG1 and IgG4 mAbs...
December 1, 2016: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27915195/hydrogen-deuterium-exchange-a-unique-and-effective-method-for-ms-fragmentation-behavior-elucidation-of-ginkgolides-and-its-application-to-systematic-research-in-ginkgo-biloba
#3
Xingliang Niu, Jun Luo, Deran Xu, Hongyan Zou, Lingyi Kong
Ginkgolides, the main active constituents of Ginkgo biloba, possess significant selectively inhibition on platelet-activating factor and pancreatic lipase and attract wide attention in pharmacological research area. In our study, an effective hydrogen/deuterium (H/D) exchange method was developed by exchanging the α-Hs of lactone groups in ginkgolides with Ds, which was very useful for the elucidation of the fragmentation patterns of ginkgolides in Quadrupole Time-of-flight Mass Spectrometry (Q-TOF-MS), especially in accurately distinguishing the type and position of substituent in framework of ginkgolides...
November 26, 2016: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/27879668/structure-functional-basis-of-ion-transport-in-sodium-calcium-exchanger-ncx-proteins
#4
REVIEW
Moshe Giladi, Reut Shor, Michal Lisnyansky, Daniel Khananshvili
The membrane-bound sodium-calcium exchanger (NCX) proteins shape Ca(2+) homeostasis in many cell types, thus participating in a wide range of physiological and pathological processes. Determination of the crystal structure of an archaeal NCX (NCX_Mj) paved the way for a thorough and systematic investigation of ion transport mechanisms in NCX proteins. Here, we review the data gathered from the X-ray crystallography, molecular dynamics simulations, hydrogen-deuterium exchange mass-spectrometry (HDX-MS), and ion-flux analyses of mutants...
November 22, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27879053/n-arylsulfonyl-indolines-as-retinoic-acid-receptor-related-orphan-receptor%C3%A2-%C3%AE-ror%C3%AE-agonists
#5
Christelle Doebelin, Rémi Patouret, Ruben D Garcia-Ordonez, Mi Ra Chang, Venkatasubramanian Dharmarajan, Dana S Kuruvilla, Scott J Novick, Li Lin, Michael D Cameron, Patrick R Griffin, Theodore M Kamenecka
The nuclear retinoic acid receptor-related orphan receptor γ (RORγ; NR1F3) is a key regulator of inflammatory gene programs involved in T helper 17 (TH 17) cell proliferation. As such, synthetic small-molecule repressors (inverse agonists) targeting RORγ have been extensively studied for their potential as therapeutic agents for various autoimmune diseases. Alternatively, enhancing TH 17 cell proliferation through activation (agonism) of RORγ may boost an immune response, thereby offering a potentially new approach in cancer immunotherapy...
December 6, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27870250/new-insights-into-interactions-between-the-nucleotide-binding-domain-of-cftr-and-keratin-8
#6
Aiswarya Premchandar, Anna Kupniewska, Arkadiusz Bonna, Grazyna Faure, Tomasz Fraczyk, Ariel Roldan, Brice Hoffmann, Mélanie Faria da Cunha, Harald Herrmann, Gergely L Lukacs, Aleksander Edelman, Michał Dadlez
The intermediate filament protein keratin 8 (K8) interacts with the nucleotide-binding domain 1 (NBD1) of the cystic fibrosis transmembrane regulator (CFTR) with phenylalanine 508 deletion (ΔF508), and this interaction hampers the biogenesis of functional ΔF508-CFTR and its insertion into the plasma membrane. Interruption of this interaction may constitute a new therapeutic target for cystic fibrosis patients bearing the ΔF508 mutation. Here we aimed to determine the binding surface between these two proteins, to facilitate the design of the interaction inhibitors...
November 21, 2016: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/27851982/interdomain-electron-transfer-in-cellobiose-dehydrogenase-is-governed-by-surface-electrostatics
#7
Alan Kadek, Daniel Kavan, Julien Marcoux, Johann Stojko, Alfons K G Felice, Sarah Cianférani, Roland Ludwig, Petr Halada, Petr Man
BACKGROUND: Cellobiose dehydrogenase (CDH) is a fungal extracellular oxidoreductase which fuels lytic polysaccharide monooxygenase with electrons during cellulose degradation. Interdomain electron transfer between the flavin and cytochrome domain in CDH, preceding the electron flow to lytic polysaccharide monooxygenase, is known to be pH dependent, but the exact mechanism of this regulation has not been experimentally proven so far. METHODS: To investigate the structural aspects underlying the domain interaction in CDH, hydrogen/deuterium exchange (HDX-MS) with improved proteolytic setup (combination of nepenthesin-1 with rhizopuspepsin), native mass spectrometry with ion mobility and electrostatics calculations were used...
November 13, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27807976/a-residue-resolved-bayesian-approach-to-quantitative-interpretation-of-hydrogen-deuterium-exchange-from-mass-spectrometry-application-to-characterizing-protein-ligand-interactions
#8
Daniel John Saltzberg, Howard B Broughton, Riccardo Pellarin, Michael J Chalmers, Alfonso Espada, Jeffrey A Dodge, Bruce D Pascal, Patrick R Griffin, Christine Humblet, Andrej Sali
Characterization of interactions between proteins and other molecules is crucial for understanding the mechanisms of action of biological systems and, thus, drug discovery. An increasingly useful approach to mapping these interactions is measurement of hydrogen/deuterium exchange (HDX) using mass spectrometry (HDX-MS), which measures the time-resolved deuterium incorporation of peptides obtained by enzymatic digestion of the protein. Comparison of exchange rates between apo- and ligand-bound conditions results in a mapping of the differential HDX (ΔHDX) of the ligand...
November 3, 2016: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/27797822/the-diverse-and-expanding-role-of-mass-spectrometry-in-structural-and-molecular-biology
#9
REVIEW
Philip Lössl, Michiel van de Waterbeemd, Albert Jr Heck
The emergence of proteomics has led to major technological advances in mass spectrometry (MS). These advancements not only benefitted MS-based high-throughput proteomics but also increased the impact of mass spectrometry on the field of structural and molecular biology. Here, we review how state-of-the-art MS methods, including native MS, top-down protein sequencing, cross-linking-MS, and hydrogen-deuterium exchange-MS, nowadays enable the characterization of biomolecular structures, functions, and interactions...
October 26, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27783482/an-asymmetric-antithrombin-dimer-is-a-key-intermediate-for-polymerization-revealed-by-hydrogen-deuterium-exchange-mass-spectrometry
#10
Morten Beck Trelle, Shona H Pedersen, Eva Christina Østerlund, Jeppe Buur Madsen, Søren Risom Kristensen, Thomas J D Jørgensen
Antithrombin deficiency is associated with increased risk of venous thrombosis. In certain families this condition is caused by pathogenic polymerization of mutated antithrombin in the blood. To facilitate future development of pharmaceuticals against antithrombin polymerization an improved understanding of the polymerogenic intermediates is crucial. However, X-ray crystallography of these intermediates is severely hampered by the difficulty in obtaining well-diffracting crystals of transient and heterogeneous noncovalent protein assemblies...
October 26, 2016: Analytical Chemistry
https://www.readbyqxmd.com/read/27703196/degradation-of-redox-sensitive-proteins-including-peroxiredoxins-and-dj-1-is-promoted-by-oxidation-induced-conformational-changes-and-ubiquitination
#11
In-Kang Song, Jae-Jin Lee, Jin-Hwan Cho, Jihye Jeong, Dong-Hae Shin, Kong-Joo Lee
Reactive oxygen species (ROS) are key molecules regulating various cellular processes. However, what the cellular targets of ROS are and how their functions are regulated is unclear. This study explored the cellular proteomic changes in response to oxidative stress using H2O2 in dose- and recovery time-dependent ways. We found discernible changes in 76 proteins appearing as 103 spots on 2D-PAGE. Of these, Prxs, DJ-1, UCH-L3 and Rla0 are readily oxidized in response to mild H2O2 stress, and then degraded and active proteins are newly synthesized during recovery...
October 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27662755/hydrogen-deuterium-exchange-mass-spectrometry-in-biopharmaceutical-discovery-and-development-a-review
#12
REVIEW
Bin Deng, Cristina Lento, Derek J Wilson
Protein therapeutics have emerged as a major class of biopharmaceuticals over the past several decades, a trend that has motivated the advancement of bioanalytical technologies for protein therapeutic characterization. Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a powerful and sensitive technique that can probe the higher order structure of proteins and has been used in the assessment and development of monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs) and biosimilar antibodies. It has also been used to quantify protein-ligand, protein-receptor and other protein-protein interactions involved in signaling pathways...
October 12, 2016: Analytica Chimica Acta
https://www.readbyqxmd.com/read/27630019/characterization-of-atg38-and-nrbf2-a-fifth-subunit-of-the-autophagic-vps34-pik3c3-complex
#13
Yohei Ohashi, Nicolas Soler, Miguel García Ortegón, Lufei Zhang, Marie L Kirsten, Olga Perisic, Glenn R Masson, John E Burke, Arjen J Jakobi, Apostolos A Apostolakis, Christopher M Johnson, Maki Ohashi, Nicholas T Ktistakis, Carsten Sachse, Roger L Williams
The phosphatidylinositol 3-kinase Vps34 is part of several protein complexes. The structural organization of heterotetrameric complexes is starting to emerge, but little is known about organization of additional accessory subunits that interact with these assemblies. Combining hydrogen-deuterium exchange mass spectrometry (HDX-MS), X-ray crystallography and electron microscopy (EM), we have characterized Atg38 and its human ortholog NRBF2, accessory components of complex I consisting of Vps15-Vps34-Vps30/Atg6-Atg14 (yeast) and PIK3R4/VPS15-PIK3C3/VPS34-BECN1/Beclin 1-ATG14 (human)...
November 2016: Autophagy
https://www.readbyqxmd.com/read/27602546/computational-methods-and-challenges-in-hydrogen-deuterium-exchange-mass-spectrometry
#14
Jürgen Claesen, Tomasz Burzykowski
Hydrogen/Deuterium exchange (HDX) has been applied, since the 1930s, as an analytical tool to study the structure and dynamics of (small) biomolecules. The popularity of using HDX to study proteins increased drastically in the last two decades due to the successful combination with mass spectrometry (MS). Together with this growth in popularity, several technological advances have been made, such as improved quenching and fragmentation. As a consequence of these experimental improvements and the increased use of protein-HDXMS, large amounts of complex data are generated, which require appropriate analysis...
September 7, 2016: Mass Spectrometry Reviews
https://www.readbyqxmd.com/read/27596062/conformational-modulation-of-the-farnesoid-x-receptor-by-prenylflavonoids-insights-from-hydrogen-deuterium-exchange-mass-spectrometry-hdx-ms-fluorescence-titration-and-molecular-docking-studies
#15
Liping Yang, David Broderick, Yan Campbell, Adrian F Gombart, Jan F Stevens, Yuan Jiang, Victor L Hsu, William H Bisson, Claudia S Maier
We report on the molecular interactions of the farnesoid X receptor (FXR) with prenylflavonoids, an emerging class of FXR modulators. FXR is an attractive therapeutic target for mitigating metabolic syndromes (MetS) because FXR activates the inhibitory nuclear receptor, small heterodimer partner (SHP), thereby inhibiting both gluconeogenesis and de novo lipogenesis. We and others have shown that xanthohumol (XN), the principal prenylflavonoid of the hop plant (Humulus lupulus L.), is a FXR agonist based on its ability to affect lipid and glucose metabolism in vivo and to induces FXR target genes in biliary carcinoma cells and HEK293 cells...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27578543/rapid-conformational-analysis-of-protein-drugs-in-formulation-by-hydrogen-deuterium-exchange-mass-spectrometry
#16
Zeinab E Nazari, Marco van de Weert, George Bou-Assaf, Damian Houde, Andrew Weiskopf, Kasper D Rand
Hydrogen deuterium exchange coupled to mass spectrometry (HDX-MS) has become an established method for analysis of protein higher order structure. Here, we use HDX-MS methodology based on manual solid-phase extraction (SPE) to allow fast and simplified conformational analysis of proteins under pharmaceutically relevant formulation conditions. Of significant practical utility, the methodology allows global HDX-MS analyses to be performed without refrigeration or external cooling of the setup. In mode 1, we used dimethyl sulphoxide-containing solvents for SPE, allowing the HDX-MS analysis to be performed at acceptable back-exchange levels (<30%) without the need for cooling any components of the setup...
November 2016: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27575380/understanding-the-impact-of-methionine-oxidation-on-the-biological-functions-of-igg1-antibodies-using-hydrogen-deuterium-exchange-mass-spectrometry
#17
Jingjie Mo, Qingrong Yan, Chi Kwong So, Tam Soden, Michael J Lewis, Ping Hu
Hydrogen/deuterium exchange mass spectrometry (HDX MS) was used in two case studies to evaluate the impact of methionine (Met) oxidation on the biological functions of IgG1 antibodies. In the first case study, linear correlations were observed between the oxidation of the conserved Fc methionine residues and the loss of neonatal Fc receptor (FcRn) binding and complement-dependent cytotoxicity (CDC) activity. Both heavy chain (HC) residues Met257 and Met433 were located near the FcRn binding interface as indicated by HDX MS and structural modeling; however, HC Met257 oxidation was further demonstrated to have a more significant impact on FcRn binding than HC Met433 oxidation...
October 4, 2016: Analytical Chemistry
https://www.readbyqxmd.com/read/27573935/application-of-amide-hydrogen-deuterium-exchange-mass-spectrometry-for-epitope-mapping-in-human-cystatin-c
#18
Martyna Prądzińska, Izabela Behrendt, Juan Astorga-Wells, Aleksandr Manoilov, Roman A Zubarev, Aleksandra S Kołodziejczyk, Sylwia Rodziewicz-Motowidło, Paulina Czaplewska
Human cystatin C (hCC) is a small cysteine protease inhibitor whose oligomerization by propagated domain swapping is linked to certain neurological disorders. One of the ways to prevent hCC dimerization and fibrillogenesis is to enable its interaction with a proper antibody. Herein, the sites of interaction of hCC with dimer-preventing mouse monoclonal anti-hCC antibodies Cyst28 are studied and compared with the binding sites found for mAb Cyst10 that has almost no effect on hCC dimerization. In addition, hCC epitopes in complexes with native polyclonal antibodies extracted from human serum were studied...
December 2016: Amino Acids
https://www.readbyqxmd.com/read/27569733/comparative-higher-order-structure-analysis-of-antibody-biosimilars-using-combined-bottom-up-and-top-down-hydrogen-deuterium-exchange-mass-spectrometry
#19
Jingxi Pan, Suping Zhang, Christoph H Borchers
Hydrogen/deuterium exchange (HDX) coupled with mass spectrometry (MS) is a powerful technique for higher-order structural characterization of antibodies. Although the peptide-based bottom-up HDX approach and the protein-based top-down HDX approach have complementary advantages, the work done so far on biosimilars has involved only one or the other approach. Herein we have characterized the structures of two bevacizumab (BEV) biosimilars and compared them to the reference BEV using both methods. A sequence coverage of 87% was obtained for the heavy chain and 74% for the light chain in the bottom-up approach...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27552080/conformational-insight-into-multi-protein-signaling-assemblies-by-hydrogen-deuterium-exchange-mass-spectrometry
#20
Rane A Harrison, John R Engen
Hydrogen-deuterium exchange (HDX) mass spectrometry (MS) can provide information about proteins that can be challenging to obtain by other means. Structure/function relationships, binding interactions, and the effects of modification have all been measured with HDX MS for a diverse and growing array of signaling proteins and multiprotein signaling complexes. As a result of hardware and software improvements, receptors and complexes involved in cellular signaling-including those associated with membranes-can now be studied...
August 20, 2016: Current Opinion in Structural Biology
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