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hydrogen deuterium exchange

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https://www.readbyqxmd.com/read/28919439/pih1p-tah1p-puts-a-lid-on-hexameric-aaa-atpases-rvb1-2p
#1
Shaoxiong Tian, Ge Yu, Huan He, Yu Zhao, Peilu Liu, Alan G Marshall, Borries Demeler, Scott M Stagg, Hong Li
The Saccharomyces cerevisiae (Sc) R2TP complex affords an Hsp90-mediated and nucleotide-driven chaperone activity to proteins of small ribonucleoprotein particles (snoRNPs). The current lack of structural information on the ScR2TP complex, however, prevents a mechanistic understanding of this biological process. We characterized the structure of the ScR2TP complex made up of two AAA+ ATPases, Rvb1/2p, and two Hsp90 binding proteins, Tah1p and Pih1p, and its interaction with the snoRNP protein Nop58p by a combination of analytical ultracentrifugation, isothermal titration calorimetry, chemical crosslinking, hydrogen-deuterium exchange, and cryoelectron microscopy methods...
August 24, 2017: Structure
https://www.readbyqxmd.com/read/28911221/chemical-basis-for-deuterium-labeling-of-fat-and-nadph
#2
Zhaoyue Zhang, Li Chen, Ling Liu, Xiaoyang Su, Joshua D Rabinowitz
Much understanding of metabolism is based on monitoring chemical reactions in cells with isotope tracers. For this purpose, 13C is well suited due to its stable incorporation into biomolecules and minimal kinetic isotope effect. For redox reactions, however, deuterium tracing can provide valuable additional information. To date, studies examining NADPH production with deuterated carbon sources have failed to account for roughly half of NADPH's redox active hydrogen. Here we show that the missing hydrogen is the result of enzyme-catalyzed H-D exchange between water and NADPH...
September 14, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28905070/sodium-cationized-carbohydrate-gas-phase-fragmentation-chemistry-influence-of-glycosidic-linkage-position
#3
Jordan M Rabus, Maha T Abutokaikah, Reginald T Ross, Benjamin J Bythell
We investigate the gas-phase structures and fragmentation chemistry of two isomeric sodium-cationized carbohydrates using combined tandem mass spectrometry, hydrogen/deuterium exchange experiments, and computational methods. Our model systems are the glucose-based disaccharide analytes cellobiose (β-d-glucopyranosyl-(1 → 4)-d-glucose) and gentiobiose (β-d-glucopyranosyl-(1 → 6)-d-glucose). These analytes show substantially different tandem mass spectra. We characterize the rate-determining barriers to both the glycosidic and structurally-informative cross-ring bond cleavages...
September 14, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28901129/peptide-level-interactions-between-proteins-and-small-molecule-drug-candidates-by-hdx-ms-plimstex-and-modified-suprex-the-example-of-apoe3
#4
Hanliu Wang, Don L Rempel, Daryl E Giblin, Carl Frieden, Michael L Gross
We describe a platform utilizing two methods based on hydrogen-deuterium exchange (HDX) coupled with mass spectrometry (MS) to characterize interactions between a protein and a small-molecule ligand. The model system is apolipoprotein E3 (apoE3) and a small-molecule drug candidate. We extended PLIMSTEX (protein-ligand interactions by mass spectrometry, titration, and H/D Exchange) to the regional level by incorporating enzymatic digestion to acquire binding information for peptides. In a single experiment, we not only identified putative binding sites, but also obtained affinities of 6...
September 13, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28900091/-secondary-structure-of-a%C3%AE-1-16-complexes-with-zinc-a-study-in-the-gas-phase-using-deuterium-hydrogen-exchange-and-ultra-high-resolution-mass-spectrometry
#5
Yu I Kostyukevich, A S Kononikhin, M I Indeykina, I A Popov, K V Bocharov, A I Spassky, S A Kozin, A A Makarov, E N Nikolaev
Complexes of peptide fragment 1-16 of beta-amyloid with transition metals play an important role in the development of a broad class of neurodegenerative diseases, which determines the interest in investigating the structures of these complexes. In this work, we have applied the method of the deuterium/hydrogen exchange in combination with ultra-high-resolution mass spectrometry to study conformational changes in (1-16) beta-amyloid peptide induced by binding of zinc(II) atoms. The efficiency of the deuterium/hydrogen exchange depended on the number of zinc atoms bound to the peptide and on the temperature of the ionization source region...
July 2017: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/28890360/synergistic-regulation-of-coregulator-nuclear-receptor-interaction-by-ligand-and-dna
#6
Ian Mitchelle S de Vera, Jie Zheng, Scott Novick, Jinsai Shang, Travis S Hughes, Richard Brust, Paola Munoz-Tello, William J Gardner, David P Marciano, Xiangming Kong, Patrick R Griffin, Douglas J Kojetin
Nuclear receptor (NR) transcription factors bind various coreceptors, small-molecule ligands, DNA response element sequences, and transcriptional coregulator proteins to affect gene transcription. Small-molecule ligands and DNA are known to influence receptor structure, coregulator protein interaction, and function; however, little is known on the mechanism of synergy between ligand and DNA. Using quantitative biochemical, biophysical, and solution structural methods, including (13)C-detected nuclear magnetic resonance and hydrogen/deuterium exchange (HDX) mass spectrometry, we show that ligand and DNA cooperatively recruit the intrinsically disordered steroid receptor coactivator-2 (SRC-2/TIF2/GRIP1/NCoA-2) receptor interaction domain to peroxisome proliferator-activated receptor gamma-retinoid X receptor alpha (PPARγ-RXRα) heterodimer and reveal the binding determinants of the complex...
August 23, 2017: Structure
https://www.readbyqxmd.com/read/28874374/structure-and-dynamics-of-fosa-mediated-fosfomycin-resistance-in-klebsiella-pneumoniae-and-escherichia-coli
#7
Erik H Klontz, Adam D Tomich, Sebastian Günther, Justin A Lemkul, Daniel Deredge, Zach Silverstein, JoAnna F Shaw, Christi McElheny, Yohei Doi, Patrick Wintrode, Alexander D MacKerell, Nicolas Sluis-Cremer, Eric J Sundberg
Fosfomycin exhibits broad-spectrum antibacterial activity, and is being re-evaluated for the treatment of extensively drug-resistant pathogens. Its activity in Gram-negatives, however, can be compromised by expression of FosA, a metal-dependent transferase that catalyzes the conjugation of glutathione to fosfomycin, rendering the antibiotic inactive. In this study, we solved the crystal structures of two of the most clinically relevant FosA enzymes: plasmid-encoded FosA3 from Escherichia coli and chromosomally-encoded FosA from Klebsiella pneumoniae (FosA(KP))...
September 5, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28867612/achieving-a-graded-immune-response-btk-adopts-a-range-of-active-inactive-conformations-dictated-by-multiple-interdomain-contacts
#8
Raji E Joseph, Thomas E Wales, D Bruce Fulton, John R Engen, Amy H Andreotti
Capturing the functionally relevant forms of dynamic, multidomain proteins is extremely challenging. Bruton's tyrosine kinase (BTK), a kinase essential for B and mast cell function, has stubbornly resisted crystallization in its full-length form. Here, nuclear magnetic resonance and hydrogen-deuterium exchange mass spectrometry show that BTK adopts a closed conformation in dynamic equilibrium with open, active conformations. BTK lacks the phosphotyrosine regulatory tail of the SRC kinases, yet nevertheless achieves a phosphotyrosine-independent C-terminal latch...
August 10, 2017: Structure
https://www.readbyqxmd.com/read/28864531/multiple-proteolytic-events-in-caspase-6-self-activation-impact-conformations-of-discrete-structural-regions
#9
Kevin B Dagbay, Jeanne A Hardy
Caspase-6 is critical to the neurodegenerative pathways of Alzheimer's, Huntington's, and Parkinson's diseases and has been identified as a potential molecular target for treatment of neurodegeneration. Thus, understanding the global and regional changes in dynamics and conformation provides insights into the unique properties of caspase-6 that may contribute to achieving control of its function. In this work, hydrogen/deuterium exchange MS (H/DX-MS) was used to map the local changes in the conformational flexibility of procaspase-6 at the discrete states that reflect the series of cleavage events that ultimately lead to the fully active, substrate-bound state...
September 1, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28837163/a-31-residue-peptide-induces-aggregation-of-tau-s-microtubule-binding-region-in-cells
#10
Jan Stöhr, Haifan Wu, Mimi Nick, Yibing Wu, Manasi Bhate, Carlo Condello, Noah Johnson, Jeffrey Rodgers, Thomas Lemmin, Srabasti Acharya, Julia Becker, Kathleen Robinson, Mark J S Kelly, Feng Gai, Gerald Stubbs, Stanley B Prusiner, William F DeGrado
The self-propagation of misfolded conformations of tau underlies neurodegenerative diseases, including Alzheimer's. There is considerable interest in discovering the minimal sequence and active conformational nucleus that defines this self-propagating event. The microtubule-binding region, spanning residues 244-372, reproduces much of the aggregation behaviour of tau in cells and animal models. Further dissection of the amyloid-forming region to a hexapeptide from the third microtubule-binding repeat resulted in a peptide that rapidly forms fibrils in vitro...
September 2017: Nature Chemistry
https://www.readbyqxmd.com/read/28829606/influence-of-intramolecular-charge-transfer-and-nuclear-quantum-effects-on-intramolecular-hydrogen-bonds-in-azopyrimidines
#11
Katerina Bartova, Lucie Čechová, Eliska Prochazkova, Ondrej Socha, Zlatko Janeba, Martin Dracinsky
Intramolecular hydrogen bonds (IMHBs) in 5-azopyrimidines are investigated by NMR spectroscopy and DFT computations that involve nuclear quantum effects. A series of substituted 5-phenylazopyrimidines with one or two hydrogen bond donors able to form IMHBs with the azo group is prepared by azo coupling. The barrier of interconversion between two rotamers of the compounds with two possible IMHBs is determined by variable temperature NMR spectroscopy and it is demonstrated that the barrier is significantly affected by intramolecular charge transfer...
August 22, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28827170/modulation-of-aba-signaling-by-altering-vxg%C3%AE-l-motif-of-pp2cs-in-oryza-sativa
#12
Seungsu Han, Myung Ki Min, Su-Youn Lee, Chae Woo Lim, Nikita Bhatnagar, Yeongmok Lee, Donghyuk Shin, Ka Young Chung, Sung Chul Lee, Beom-Gi Kim, Sangho Lee
The abscisic acid (ABA) signaling pathway is regulated by clade A type 2C protein phosphatases (PP2CAs) in plants. In the presence of ABA, PP2Cs release stress/ABA-activated protein kinases by binding to ABA-bound receptors (PYL/RCARs) for activation. Although the wedging tryptophan in PP2Cs is critical in the interaction with PYL/RCARs in Arabidopsis and rice, it remains elusive as to how other interface regions are involved in the interaction. Here, we report the identification of a conserved region on PP2Cs, termed the VxGΦL motif, which modulates the interaction with PYL/RCARs through its second and fourth residues...
September 12, 2017: Molecular Plant
https://www.readbyqxmd.com/read/28821744/exploring-the-sequence-based-prediction-of-folding-initiation-sites-in-proteins
#13
Daniele Raimondi, Gabriele Orlando, Rita Pancsa, Taushif Khan, Wim F Vranken
Protein folding is a complex process that can lead to disease when it fails. Especially poorly understood are the very early stages of protein folding, which are likely defined by intrinsic local interactions between amino acids close to each other in the protein sequence. We here present EFoldMine, a method that predicts, from the primary amino acid sequence of a protein, which amino acids are likely involved in early folding events. The method is based on early folding data from hydrogen deuterium exchange (HDX) data from NMR pulsed labelling experiments, and uses backbone and sidechain dynamics as well as secondary structure propensities as features...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28813004/lactose-binding-induces-opposing-dynamics-changes-in-human-galectins-revealed-by-nmr-based-hydrogen-deuterium-exchange
#14
Chih-Ta Henry Chien, Meng-Ru Ho, Chung-Hung Lin, Shang-Te Danny Hsu
Galectins are β-galactoside-binding proteins implicated in a myriad of biological functions. Despite their highly conserved carbohydrate binding motifs with essentially identical structures, their affinities for lactose, a common galectin inhibitor, vary significantly. Here, we aimed to examine the molecular basis of differential lactose affinities amongst galectins using solution-based techniques. Consistent dissociation constants of lactose binding were derived from nuclear magnetic resonance (NMR) spectroscopy, intrinsic tryptophan fluorescence, isothermal titration calorimetry and bio-layer interferometry for human galectin-1 (hGal1), galectin-7 (hGal7), and the N-terminal and C-terminal domains of galectin-8 (hGal8(NTD) and hGal8(CTD), respectively)...
August 16, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28809482/structural-dynamics-of-15-lipoxygenase-2-via-hydrogen-deuterium-exchange
#15
Kristin Diane Droege, Mary E Keithly, Charles R Sanders, Richard N Armstrong, Matthew K Thompson
Eicosanoids are inflammatory signaling lipids that are biosynthesized in response to cellular injury or threat. They were originally thought to be pro-inflammatory molecules, but at least one sub-class, the lipoxins, are able to resolve inflammation. The first step in lipoxin synthesis is the oxygenation of arachidonic acid by 15-Lipoxygenase (15-LOX). 15-LOX contains two domains: a Ca2+ binding PLAT domain and a catalytic domain. 15-LOX is a soluble cytosolic protein until Ca2+ binding to the PLAT domain promotes translocation to the membrane surface...
August 15, 2017: Biochemistry
https://www.readbyqxmd.com/read/28808005/conformational-dynamics-of-1-deoxy-d-xylulose-5-phosphate-synthase-on-ligand-binding-revealed-by-h-d-exchange-ms
#16
Jieyu Zhou, Luying Yang, Alicia DeColli, Caren Freel Meyers, Natalia S Nemeria, Frank Jordan
The enzyme 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) is a key enzyme in the methylerythritol 4-phosphate pathway and is a target for the development of antibiotics, herbicides, and antimalarial drugs. DXPS catalyzes the formation of 1-deoxy-d-xylulose 5-phosphate (DXP), a branch point metabolite in isoprenoid biosynthesis, and is also used in the biosynthesis of thiamin (vitamin B1) and pyridoxal (vitamin B6). Previously, we found that DXPS is unique among the superfamily of thiamin diphosphate (ThDP)-dependent enzymes in stabilizing the predecarboxylation intermediate, C2-alpha-lactyl-thiamin diphosphate (LThDP), which has subsequent decarboxylation that is triggered by d-glyceraldehyde 3-phosphate (GAP)...
August 29, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28803776/mechanism-of-enzyme-repair-by-the-aaa-chaperone-rubisco-activase
#17
Javaid Y Bhat, Goran Miličić, Gabriel Thieulin-Pardo, Andreas Bracher, Andrew Maxwell, Susanne Ciniawsky, Oliver Mueller-Cajar, John R Engen, F Ulrich Hartl, Petra Wendler, Manajit Hayer-Hartl
How AAA+ chaperones conformationally remodel specific target proteins in an ATP-dependent manner is not well understood. Here, we investigated the mechanism of the AAA+ protein Rubisco activase (Rca) in metabolic repair of the photosynthetic enzyme Rubisco, a complex of eight large (RbcL) and eight small (RbcS) subunits containing eight catalytic sites. Rubisco is prone to inhibition by tight-binding sugar phosphates, whose removal is catalyzed by Rca. We engineered a stable Rca hexamer ring and analyzed its functional interaction with Rubisco...
September 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28798232/conformational-characterization-of-nerve-growth-factor-%C3%AE-reveals-that-its-regulatory-pro-part-domain-stabilizes-three-loop-regions-in-its-mature-part
#18
Esben Trabjerg, Fredrik Kartberg, Søren Christensen, Kasper D Rand
Nerve growth factor-β (NGF) is essential for correct development of the nervous system. NGF exists both in a mature and a pro-form (proNGF). The two forms have opposing effects on neurons, in which NGF induces proliferation, while proNGF induces apoptosis via binding to a receptor complex of the common neurotrophine receptor (p75NTR) and Sortilin. Overexpression of both proNGF and Sortilin has been associated with several neurodegenerative diseases. Insights into the conformational differences between proNGF and NGF are central to a better understanding of the opposing mechanisms of action of NGF and proNGF on neurons...
August 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28797100/mapping-the-contact-surfaces-in-the-lamin-a-aimp3-complex-by-hydrogen-deuterium-exchange-ft-icr-mass-spectrometry
#19
Yeqing Tao, Pengfei Fang, Sunghoon Kim, Min Guo, Nicolas L Young, Alan G Marshall
Aminoacyl-tRNA synthetases-interacting multifunctional protein3 (AIMP3/p18) is involved in the macromolecular tRNA synthetase complex via its interaction with several aminoacyl-tRNA synthetases. Recent reports reveal a novel function of AIMP3 as a tumor suppressor by accelerating cellular senescence and causing defects in nuclear morphology. AIMP3 specifically mediates degradation of mature Lamin A (LmnA), a major component of the nuclear envelope matrix; however, the mechanism of how AIMP3 interacts with LmnA is unclear...
2017: PloS One
https://www.readbyqxmd.com/read/28792473/taxol-%C3%A2-the-first-microtubule-stabilizing-agent
#20
REVIEW
Chia-Ping Huang Yang, Susan Band Horwitz
Taxol(®), an antitumor drug with significant activity, is the first microtubule stabilizing agent described in the literature. This short review of the mechanism of action of Taxol(®) emphasizes the research done in the Horwitz' laboratory. It discusses the contribution of photoaffinity labeled analogues of Taxol(®) toward our understanding of the binding site of the drug on the microtubule. The importance of hydrogen/deuterium exchange experiments to further our insights into the stabilization of microtubules by Taxol(®) is addressed...
August 9, 2017: International Journal of Molecular Sciences
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