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Hydrogen exchange mass spectrometry

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https://www.readbyqxmd.com/read/28652337/mine-conformational-dynamics-regulate-membrane-binding-mind-interaction-and-min-oscillation
#1
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/28648608/structures-of-pgam5-provide-insight-into-active-site-plasticity-and-multimeric-assembly
#2
Apirat Chaikuad, Panagis Filippakopoulos, Sean R Marcsisin, Sarah Picaud, Martin Schröder, Shiori Sekine, Hidenori Ichijo, John R Engen, Kohsuke Takeda, Stefan Knapp
PGAM5 is a mitochondrial membrane protein that functions as an atypical Ser/Thr phosphatase and is a regulator of oxidative stress response, necroptosis, and autophagy. Here we present several crystal structures of PGAM5 including the activating N-terminal regulatory sequences, providing a model for structural plasticity, dimerization of the catalytic domain, and the assembly into an enzymatically active dodecameric form. Oligomeric states observed in structures were supported by hydrogen exchange mass spectrometry, size-exclusion chromatography, and analytical ultracentrifugation experiments in solution...
June 10, 2017: Structure
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
#3
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/28630467/computational-method-allowing-hydrogen-deuterium-exchange-mass-spectrometry-at-single-amide-resolution
#4
Chris Gessner, Wieland Steinchen, Sabrina Bédard, John J Skinner, Virgil L Woods, Thomas J Walsh, Gert Bange, Dionysios P Pantazatos
Hydrogen-deuterium exchange (HDX) coupled with mass spectrometry (HDXMS) is a rapid and effective method for localizing and determining protein stability and dynamics. Localization is routinely limited to a peptide resolution of 5 to 20 amino acid residues. HDXMS data can contain information beyond that needed for defining protein stability at single amide resolution. Here we present a method for extracting this information from an HDX dataset to generate a HDXMS protein stability fingerprint. High resolution (HR)-HDXMS was applied to the analysis of a model protein of a spectrin tandem repeat that exemplified an intuitive stability profile based on the linkage of two triple helical repeats connected by a helical linker...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28628309/dissecting-orthosteric-contacts-for-a-reverse-fragment-based-ligand-design
#5
Arun Chandramohan, Nikhil Kumar Tulsian, Ganesh Srinivasan Anand
Orthosteric sites on proteins are formed typically from non-contiguous interacting sites in three dimensional space where the composite binding interaction of a biological ligand is mediated by multiple synergistic interactions of its constituent functional groups. Through these multiple interactions, ligands stabilize both the ligand binding site and the protein fold. However, relative energetic contributions of the individual contacts in these protein-ligand interactions are difficult to resolve. Deconvolution of the contributions of these various functional groups in natural inhibitors/ligand would greatly aid in iterative fragment-based drug discovery (FBDD)...
June 19, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28627884/hdx-ms-reveals-calcium-binding-properties-and-allosteric-regulation-of-downstream-regulatory-element-antagonist-modulator-dream
#6
Jun Zhang, Jing Li, Theodore A Craig, Rajiv Kumar, Michael L Gross
Downstream regulatory element antagonist modulator (DREAM) is an EF-hand Ca2+-binding protein that also binds to specific DNA sequence, downstream regulatory elements (DRE), and thereby regulates transcription in a calcium-dependent fashion. DREAM binds to DRE in the absence of Ca2+, but detaches from DRE under Ca2+ stimulation, allowing gene expression. The Ca2+-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 Ca2+ binding properties and the subsequent conformational changes of full length DREAM...
June 19, 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
#7
Ke Sherry Li, Guodong Chen, Jingjie Mo, Richard Y-C Huang, Ekaterina G Deyanova, Brett R Beno, Steve 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...
June 16, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28611361/discovery-of-a-novel-conformational-equilibrium-in-urokinase-type-plasminogen-activator
#8
Tobias Kromann-Hansen, Eva Louise Lange, Hans Peter Sørensen, Gholamreza Hassanzadeh-Ghassabeh, Mingdong Huang, Jan K Jensen, Serge Muyldermans, Paul J Declerck, Elizabeth A Komives, Peter A Andreasen
Although trypsin-like serine proteases have flexible surface-exposed loops and are known to adopt higher and lower activity conformations, structural determinants for the different conformations have remained largely obscure. The trypsin-like serine protease, urokinase-type plasminogen activator (uPA), is central in tissue remodeling processes and also strongly implicated in tumor metastasis. We solved five X-ray crystal structures of murine uPA (muPA) in the absence and presence of allosteric molecules and/or substrate-like molecules...
June 13, 2017: Scientific Reports
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
#9
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...
May 30, 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
#10
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/28559318/a-mechanism-for-lipid-binding-to-apoe-and-the-role-of-intrinsically-disordered-regions-coupled-to-domain-domain-interactions
#11
Carl Frieden, Hanliu Wang, Chris M W Ho
Relative to the apolipoprotein E (apoE) E3 allele of the APOE gene, apoE4 strongly increases the risk for the development of late-onset Alzheimer's disease. However, apoE4 differs from apoE3 by only a single amino acid at position 112, which is arginine in apoE4 and cysteine in apoE3. It remains unclear why apoE3 and apoE4 are functionally different. Described here is a proposal for understanding the functional differences between these two isoforms with respect to lipid binding. A mechanism is proposed that is based on the full-length monomeric structure of the protein, on hydrogen-deuterium exchange mass spectrometry data, and on the role of intrinsically disordered regions to control protein motions...
May 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28550305/dynamics-and-ligand-induced-conformational-changes-in-human-prolyl-oligopeptidase-analyzed-by-hydrogen-deuterium-exchange-mass-spectrometry
#12
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/28533135/enhanced-local-disorder-in-a-clinically-elusive-von-willebrand-factor-provokes-high-affinity-platelet-clumping
#13
Alexander Tischer, Venkata R Machha, Juan P Frontroth, Maria A Brehm, Tobias Obser, Reinhard Schneppenheim, Leland Mayne, S Walter Englander, Matthew Auton
Mutation of the cysteines forming the disulfide loop of the platelet GPIbα adhesive A1 domain of von Willebrand factor (VWF) causes quantitative VWF deficiencies in the blood and von Willebrand disease. We report two cases of transient severe thrombocytopenia induced by DDAVP treatment. Cys1272Trp and Cys1458Tyr mutations identified by genetic sequencing implicate an abnormal gain-of-function phenotype, evidenced by thrombocytopenia, which quickly relapses back to normal platelet counts and deficient plasma VWF...
May 19, 2017: Journal of Molecular Biology
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
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...
May 26, 2017: Biochemistry
https://www.readbyqxmd.com/read/28490633/single-particle-electron-microscopy-structure-of-udp-glucose-glycoprotein-glucosyltransferase-suggests-a-selectivity-mechanism-for-misfolded-proteins
#18
Daniel Calles-Garcia, Meng Yang, Naoto Soya, Roberto Melero, Marie Ménade, Yukishige Ito, Javier Vargas, Gergely L Lukacs, Justin M Kollman, Guennadi Kozlov, Kalle Gehring
The enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT) mediates quality control of glycoproteins in the endoplasmic reticulum by attaching glucose to N-linked glycan of misfolded proteins. As a sensor, UGGT ensures that misfolded proteins are recognized by the lectin chaperones and do not leave the secretory pathway. The structure of UGGT and the mechanism of its selectivity for misfolded proteins have been unknown for 25 years. Here, we used negative-stain electron microscopy and small-angle X-ray scattering to determine the structure of UGGT from Drosophila melanogaster at 18 Å resolution...
May 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28488200/application-of-atmospheric-pressure-photoionization-h-d-exchange-mass-spectrometry-for-speciation-of-sulfur-containing-compounds
#19
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...
May 9, 2017: Journal of the American Society for Mass Spectrometry
https://www.readbyqxmd.com/read/28481522/rapid-hydrogen-deuterium-exchange-in-liquid-droplets
#20
Erik T Jansson, Yin-Hung Lai, Juan G Santiago, Richard N Zare
The rate of hydrogen-deuterium exchange (HDX) in aqueous droplets of phenethylamine has been determined with submillisecond temporal resolution by mass spectrometry using nanoelectrospray ionization with a theta-capillary. The average speed of the microdroplets is measured using microparticle image velocimetry. The droplet travel time is varied from 20 to 320 μs by changing the distance between the emitter and the heated inlet to the mass spectrometer and the voltage applied to the emitter source. The droplets were found to accelerate by ∼30% during their observable travel time...
May 12, 2017: Journal of the American Chemical Society
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