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hydrogen deuterium exchange

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https://www.readbyqxmd.com/read/28550305/dynamics-and-ligand-induced-conformational-changes-in-human-prolyl-oligopeptidase-analyzed-by-hydrogen-deuterium-exchange-mass-spectrometry
#1
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
#2
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 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, that quickly relapses back to normal platelet counts and deficient plasma VWF. Using surface plasmon resonance, analytical rheology, and hydrogen-deuterium exchange mass spectrometry (HXMS), we decipher mechanisms of A1-GPIbα mediated platelet adhesion and resolve dynamic secondary structure elements that regulate the binding pathway...
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
#3
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/28514451/structure-of-the-full-length-glucagon-class-b-g-protein-coupled-receptor
#4
Haonan Zhang, Anna Qiao, Dehua Yang, Linlin Yang, Antao Dai, Chris de Graaf, Steffen Reedtz-Runge, Venkatasubramanian Dharmarajan, Hui Zhang, Gye Won Han, Thomas D Grant, Raymond G Sierra, Uwe Weierstall, Garrett Nelson, Wei Liu, Yanhong Wu, Limin Ma, Xiaoqing Cai, Guangyao Lin, Xiaoai Wu, Zhi Geng, Yuhui Dong, Gaojie Song, Patrick R Griffin, Jesper Lau, Vadim Cherezov, Huaiyu Yang, Michael A Hanson, Raymond C Stevens, Qiang Zhao, Hualiang Jiang, Ming-Wei Wang, Beili Wu
The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain...
May 17, 2017: Nature
https://www.readbyqxmd.com/read/28513578/crystal-structure-of-a-multi-domain-human-smoothened-receptor-in-complex-with-a-super-stabilizing-ligand
#5
Xianjun Zhang, Fei Zhao, Yiran Wu, Jun Yang, Gye Won Han, Suwen Zhao, Andrii Ishchenko, Lintao Ye, Xi Lin, Kang Ding, Venkatasubramanian Dharmarajan, Patrick R Griffin, Cornelius Gati, Garrett Nelson, Mark S Hunter, Michael A Hanson, Vadim Cherezov, Raymond C Stevens, Wenfu Tan, Houchao Tao, Fei Xu
The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC114, using an X-ray free-electron laser source at 2.9 Å. The structure reveals a precise arrangement of three distinct domains: a seven-transmembrane helices domain (TMD), a hinge domain (HD) and an intact extracellular cysteine-rich domain (CRD)...
May 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28505408/ion-mobility-hydrogen-deuterium-exchange-and-isotope-scrambling-tools-to-aid-compound-identification-in-omics-mixtures
#6
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 duet 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 15, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28504253/dynamic-diversity-of-synthetic-supramolecular-polymers-in-water-as-revealed-by-hydrogen-deuterium-exchange
#7
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
#8
Hanliu Wang, Qin Shu, Carl Frieden, Michael L Gross
Non-enzymatic 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 other 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 12, 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
#9
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/28488849/solution-conformations-and-dynamics-of-substrate-bound-cytochrome-p450-mycg
#10
Drew R Tietz, Larissa M Podust, David H Sherman, Thomas C Pochapsky
MycG is a P450 monooxygenase that catalyzes the sequential hydroxylation and epoxidation of mycinamicin IV (M-IV), the last two steps in the biosynthesis of mycinamicin II, a macrolide antibiotic isolated from Micromonospora griseorubida. The crystal structure of MycG with M-IV bound was previously determined but showed the bound substrate in an orientation that did not rationalize the observed regiochemistry of M-IV hydroxylation. Nuclear magnetic resonance paramagnetic relaxation enhancements provided evidence of an orientation of M-IV in the MycG active site more compatible with the observed chemistry, but substrate-induced changes in the enzyme structure were not characterized...
May 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28488200/application-of-atmospheric-pressure-photoionization-h-d-exchange-mass-spectrometry-for-speciation-of-sulfur-containing-compounds
#11
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
#12
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
https://www.readbyqxmd.com/read/28481113/hydrogen-deuterium-exchange-mass-spectrometry-reveals-mechanistic-details-of-activation-of-nucleoside-diphosphate-kinases-by-oligomerization
#13
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...
May 17, 2017: Biochemistry
https://www.readbyqxmd.com/read/28481111/conformational-changes-in-active-and-inactive-states-of-human-pp2c%C3%AE-characterized-by-hydrogen-deuterium-exchange-mass-spectrometry
#14
Sharlyn J Mazur, Elyssia S Gallagher, Subrata Debnath, Stewart R Durell, Kyle W Anderson, Lisa M Miller Jenkins, Ettore Appella, Jeffrey W Hudgens
PPM serine/threonine protein phosphatases function in signaling pathways and require millimolar concentrations of Mn(2+) or Mg(2+) ions for activity. Whereas the crystal structure of human PP2Cα displayed two tightly bound Mn(2+) ions in the active site, recent investigations of PPM phosphatases have characterized the binding of a third, catalytically essential metal ion. The binding of the third Mg(2+) to PP2Cα was reported to have millimolar affinity and to be entropically driven, suggesting it may be structurally and catalytically important...
May 12, 2017: Biochemistry
https://www.readbyqxmd.com/read/28474773/miller-urey-spark-discharge-experiments-in-the-deuterium-world
#15
Geoffrey J T Cooper, Andrew J Surman, Jim McIver, Stephanie M Colón-Santos, Piotr S Gromski, Saskia Buchwald, Irene Suárez Marina, Leroy Cronin
We designed and conducted a series of primordial-soup Miller-Urey style experiments with deuterated gases and reagents to compare the spark-discharge products of a "deuterated world" with the standard reaction in the "hydrogenated world". While the deuteration of the system has little effect on the distribution of amino acid products, significant differences are seen in other regions of the product-space. Not only do we observe about 120 new species, we also see significant differences in their distribution if the two hydrogen isotope worlds are compared...
May 5, 2017: Angewandte Chemie
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
#16
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
https://www.readbyqxmd.com/read/28465180/application-of-isotope-exchange-based-mass-spectrometry-to-understand-the-mechanism-of-inhibition-of-sickle-hemoglobin-polymerization-upon-oxygenation
#17
Rajdeep Das, Amrita Mitra, Vijay Bhat, Amit Kumar Mandal
Sickle hemoglobin (HbS) polymerization initiates in the deoxy state with the binding of hydrophobic patch formed by the isopropyl group of βVal6 residue of a hemoglobin tetramer with the hydrophobic pocket of another tetramer, whose hydrophobic patch binds to the hydrophobic groove of a third molecule. Subsequent elongation of a single stranded polymer followed by the formation of a double strand and finally combination of seven such pairs of double strands results in a fourteen stranded fibrous polymer. Precipitation of this fiber inside the erythrocytes results in sickling of red blood cells...
April 29, 2017: Journal of Structural Biology
https://www.readbyqxmd.com/read/28455203/deuterium-kinetic-isotope-effect-dkie-in-copper-induced-ldl-peroxidation-interrelated-effects-of-on-inhibition-and-propagation
#18
Ilya Pinchuk, Dov Lichtenberg
LDL peroxidation plays a major role in many physiological and pathophysiological processes. The mechanisms of LDL peroxidation induced by transition metal ions have therefore been studied intensively. It has been proposed that the mechanism involves free radical production that occurs via decomposition of hydroperoxides. This, in turn, requires the cleavage of O-H bonds. Cleavage of O-D bond is slower and comparison of the kinetics in D2O to the kinetics in H2O is therefore a straightforward way to test this aspect of the alleged mechanism...
June 2017: Chemistry and Physics of Lipids
https://www.readbyqxmd.com/read/28453785/structural-and-functional-characterization-of-the-pnkp-xrcc4-ligiv-dna-repair-complex
#19
R Daniel Aceytuno, Cortt G Piett, Zahra Havali-Shahriari, Ross A Edwards, Martial Rey, Ruiqiong Ye, Fatima Javed, Shujuan Fang, Rajam Mani, Michael Weinfeld, Michal Hammel, John A Tainer, David C Schriemer, Susan P Lees-Miller, J N Mark Glover
Non-homologous end joining (NHEJ) repairs DNA double strand breaks in non-cycling eukaryotic cells. NHEJ relies on polynucleotide kinase/phosphatase (PNKP), which generates 5΄-phosphate/3΄-hydroxyl DNA termini that are critical for ligation by the NHEJ DNA ligase, LigIV. PNKP and LigIV require the NHEJ scaffolding protein, XRCC4. The PNKP FHA domain binds to the CK2-phosphorylated XRCC4 C-terminal tail, while LigIV uses its tandem BRCT repeats to bind the XRCC4 coiled-coil. Yet, the assembled PNKP-XRCC4-LigIV complex remains uncharacterized...
April 27, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28451953/observing-proton-transfer-reactions-inside-the-maldi-plume-experimental-and-theoretical-insight-into-maldi-gas-phase-reactions
#20
Mario F Mirabelli, Renato Zenobi
We evaluated the contribution of gas-phase in-plume proton transfer reactions to the formation of protonated and deprotonated molecules in the MALDI process. A split sample holder was used to separately deposit two different samples, which avoids any mixing during sample preparation. The two samples were brought very close to each other and desorbed/ionized by the same laser pulse. By using a combination of deuterated and non-deuterated matrices, it was possible to observe exclusively in-plume proton transfer processes...
April 27, 2017: Journal of the American Society for Mass Spectrometry
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