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hydrogen deuterium exchange

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https://www.readbyqxmd.com/read/27903652/prepore-stability-controls-productive-folding-of-the-bam-independent-multimeric-outer-membrane-secretin-puld
#1
Ingrid Guilvout, Sébastien Brier, Mohamed Chami, Véronique Hourdel, Olivera Francetic, Anthony P Pugsley, Julia Chamot-Rooke, Gerard H M Huysmans
Members of a group of multimeric secretion pores that assemble independently of any known membrane-embedded insertase in Gram-negative bacteria fold into a prepore before membrane-insertion occurs. The mechanisms and the energetics that drive the folding of these proteins are poorly understood. Here, equilibrium unfolding and hydrogen/deuterium exchange monitored by mass spectrometry indicated that a loss of 4-5 kJ/mol/protomer in the N3-domain that is peripheral to the membrane-spanning C-domain in the dodecameric secretin PulD, the founding member of this class, prevents pore formation by destabilizing the prepore into a poorly structured dodecamer as visualized by electron microscopy...
November 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27892738/methodological-approaches-and-insights-on-protein-aggregation-in-biological-systems
#2
Paulo Bastos, Fábio Trindade, Adelino Leite-Moreira, Inês Falcão-Pires, Rita Ferreira, Rui Vitorino
The proper folding of native proteins is critical and dynamic, but inherently unstable. Therefore, proteins eventually end up adopting misfolded conformations which compromise their function and may even trigger aggregation. Risk factors for neurodegenerative, metabolic and heart diseases compromise cellular protein quality-control systems, promoting protein aggregation. Multiple protein post-translational modifications dynamically regulate protein aggregation and disaggregation in a very complex, intricate and delicate balance...
November 28, 2016: Expert Review of Proteomics
https://www.readbyqxmd.com/read/27889293/stability-behaviour-of-antiretroviral-drugs-and-their-combinations-5-characterization-of-novel-degradation-products-of-abacavir-sulfate-by-mass-and-nuclear-magnetic-resonance-spectrometry
#3
Moolchand Kurmi, Archana Sahu, Saranjit Singh
In the present study, degradation behaviour of abacavir sulfate was evaluated in solution and solid stress conditions. Solution state studies resulted in formation of eleven degradation products; of which two were also formed on solid stress. The same were separated by high performance liquid chromatography. They were characterized using liquid chromatography-high resolution mass spectrometry, liquid chromatography-multistage mass spectrometry and hydrogen/deuterium exchange mass spectrometry data. Additionally, seven degradation products were isolated and subjected to 1D and 2D nuclear magnetic resonance studies for their structural confirmation...
November 5, 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...
November 23, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27872189/biophysical-evidence-for-intrinsic-disorder-in-the-c-terminal-tails-of-the-egfr-and-her3-receptor-tyrosine-kinases
#6
Theodore R Keppel, Kwabena Sarpong, Elisa M Murray, John Monsey, Jian Zhu, Ron Bose
The EGFR/ErbB family of receptor tyrosine kinases includes oncogenes important in the progression of breast and other cancers and they are targets for many drug development strategies. Each member of the ErbB family possesses a unique, structurally uncharacterized C-terminal tail that plays an important role in autophosphorylation and signal propagation. To determine if these C-terminal tails are intrinsically disordered regions, we conducted a battery of biophysical experiments on the EGFR and HER3 tails. Using hydrogen/deuterium exchange mass spectrometry, we measured the conformational dynamics of intracellular half constructs and compared the tails to the ordered kinase domains...
November 21, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27870837/ubiquitin-utilizes-an-acidic-surface-patch-to-alter-chromatin-structure
#7
Galia T Debelouchina, Karola Gerecht, Tom W Muir
Ubiquitylation of histone H2B, associated with gene activation, leads to chromatin decompaction through an unknown mechanism. We used a hydrogen-deuterium exchange strategy coupled with NMR spectroscopy to map the ubiquitin surface responsible for its structural effects on chromatin. Our studies revealed that a previously uncharacterized acidic patch on ubiquitin comprising residues Glu16 and Glu18 is essential for decompaction. These residues mediate promiscuous electrostatic interactions with the basic histone proteins, potentially positioning the ubiquitin moiety as a dynamic 'wedge' that prevents the intimate association of neighboring nucleosomes...
November 21, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27870250/new-insights-into-interactions-between-the-nucleotide-binding-domain-of-cftr-and-keratin-8
#8
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/27862198/synthesis-and-selective-2-h-13-c-and-15-n-labeling-of-the-tau-protein-binder-thk-523
#9
Karoline T Neumann, Anders T Lindhardt, Benny Bang-Andersen, Troels Skrydstrup
A new synthetic route to the Tau binder, THK-523, is disclosed herein, which can easily be adapted to (13) C- and D-isotope labeling. The synthesis proceeds via two key reactions, namely, a Pd-catalyzed carbonylative Sonogashira coupling and a reductive ring-closing step with hydrogen or deuterium gas. By carrying out these reactions in a 2-chamber reactor we reported previously, ex situ-generated carbon monoxide and hydrogen/deuterium can be applied in stoichiometric quantities, thereby facilitating isotope labeling of this Tau-binding compound...
November 13, 2016: Journal of Labelled Compounds & Radiopharmaceuticals
https://www.readbyqxmd.com/read/27851982/interdomain-electron-transfer-in-cellobiose-dehydrogenase-is-governed-by-surface-electrostatics
#10
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/27846722/-utilization-of-hydrogen-deuterium-exchange-in-biopharmaceutical-industry
#11
D Coufalová, B Vojtěšek, L Hernychova
BACKGROUND: The development of biopharmaceutics is the fastest growing segment of the present pharmaceutical industry. The analysis of proteins therapeutics is a challenging task due to their large size and complexity of spatial structure. Any changes in the primary, secondary, tertiary or quaternary protein structure can have huge impact on their function, efficiency and toxicity. Mass spectrometry proved itself to be a powerful tool for analysis of primary protein structure (amino acid sequence) and thanks to the development of new techniques in last years it is able to analyse higher order protein structures...
2016: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/27845431/ligand-mediated-changes-in-conformational-dynamics-of-npma-implications-for-ribosomal-interactions
#12
Nilofer Husain, Nikhil Kumar Tulsian, Wang Loo Chien, Sushant Suresh, Ganesh Srinivasan Anand, J Sivaraman
Aminoglycosides are broad-spectrum antibiotics that bind to the 30S ribosomal subunit (30S) of bacteria and disrupt protein translation. NpmA, a structurally well-characterized methyltransferase identified in an E. coli clinical isolate, catalyzes methylation of 30S at A1408 of the 16S rRNA and confers aminoglycoside resistance. Using sucrose cushion centrifugation and isothermal titration calorimetry, we first confirmed the binding between NpmA and 30S. Next, we performed amide Hydrogen/Deuterium Exchange Mass Spectrometry (HDXMS) of apo NpmA and in the presence and absence of SAM/SAH...
November 15, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27832483/7tm-domain-structure-of-adhesion-gpcrs
#13
Chris de Graaf, Saskia Nijmeijer, Steffen Wolf, Oliver P Ernst
Schematic presentation of the overall adhesion G Protein-Coupled Receptor (aGPCR) structure and functional domains, covering an extracellular N-terminal fragment (NTF), a membrane-spanning C-terminal fragment (CTF) and a GPCR proteolysis site (GPS). (Left side) aGPCR model constructed based on the seven-transmembrane (7TM) structure (blue) of secretin family glucagon receptor (GCGR) (PDB, 4L6R) [11] and the GPCR autoproteolysis inducing (GAIN) domain (magenta) structure of latrophilin 1 (PDB, 4DLQ) [9]...
2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27809489/structural-insights-into-the-drosophila-melanogaster-retinol-dehydrogenase-a-member-of-the-short-chain-dehydrogenase-reductase-family
#14
Lukas Hofmann, Yaroslav Tsybovsky, Nathan S Alexander, Darwin Babino, Nicole Yishi Leung, Craig Montell, Surajit Banerjee, Johannes von Lintig, Krzysztof Palczewski
The 11-cis-retinylidene chromophore of visual pigments isomerizes upon interaction with a photon, initiating a downstream cascade of signaling events that ultimately lead to visual perception. 11-cis-Retinylidene is regenerated through the enzymatic transformations collectively called visual cycle. The first and rate-limiting enzymatic reaction within this cycle, i.e. the reduction of all-trans-retinal to all-trans-retinol, is catalyzed by retinol dehydrogenases. Here, we solved the structure of Drosophila melanogaster photoreceptor retinol dehydrogenase (PDH) isoform C (PDHc) that belongs to the short-chain dehydrogenase/reductase (SDR) family...
November 3, 2016: Biochemistry
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
#15
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/27806276/the-ph-dependent-trigger-in-diphtheria-toxin-t-domain-comes-with-a-safety-latch
#16
Mykola V Rodnin, Jing Li, Michael L Gross, Alexey S Ladokhin
Protein-side-chain protonation, coupled to conformational rearrangements, is one way of regulating physiological function caused by changes in protein environment. Specifically, protonation of histidine residues has been implicated in pH-dependent conformational switching in several systems, including the diphtheria toxin translocation (T) domain, which is responsible for the toxin's cellular entry via the endosomal pathway. Our previous studies a) identified protonation of H257 as a major component of the T domain's conformational switch and b) suggested the possibility of a neighboring H223 acting as a modulator, affecting the protonation of H257 and preventing premature conformational changes outside the endosome...
November 1, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27797822/the-diverse-and-expanding-role-of-mass-spectrometry-in-structural-and-molecular-biology
#17
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/27791120/structural-flexibility-at-a-major-conserved-antibody-target-on-hepatitis-c-virus-e2-antigen
#18
Leopold Kong, David E Lee, Rameshwar U Kadam, Tong Liu, Erick Giang, Travis Nieusma, Fernando Garces, Netanel Tzarum, Virgil L Woods, Andrew B Ward, Sheng Li, Ian A Wilson, Mansun Law
Hepatitis C virus (HCV) is a major cause of liver disease, affecting over 2% of the world's population. The HCV envelope glycoproteins E1 and E2 mediate viral entry, with E2 being the main target of neutralizing antibody responses. Structural investigations of E2 have produced templates for vaccine design, including the conserved CD81 receptor-binding site (CD81bs) that is a key target of broadly neutralizing antibodies (bNAbs). Unfortunately, immunization with recombinant E2 and E1E2 rarely elicits sufficient levels of bNAbs for protection...
October 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27783482/an-asymmetric-antithrombin-dimer-is-a-key-intermediate-for-polymerization-revealed-by-hydrogen-deuterium-exchange-mass-spectrometry
#19
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/27778433/extending-the-domain-averaged-exchange-correlation-energies-within-the-context-of-the-mc-qtaim-tracing-subtle-variations-induced-by-isotope-substitution
#20
Mohammad Goli, Shant Shahbazian
Recently, it has been demonstrated that the domain-averaged exchange-correlation energies, V(xc) , are capable of tracing the covalent character of atom-atom interactions unequivocally and thus pave the way for detailed bonding analysis within the context of the quantum theory of atoms in molecules (QTAIM) [M. García-Revilla, E. Francisco, P. L. Popelier, A. Martín Pendás, ChemPhysChem 2013, 14, 1211-1218]. Herein, the concept of V(xc) is extended within the context of the newly developed multicomponent QTAIM (MC-QTAIM)...
October 25, 2016: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
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