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Hydrogen-Deuterium Exchange MS

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https://www.readbyqxmd.com/read/29035497/conformational-dynamics-of-dna-binding-and-cas3-recruitment-by-the-crispr-rna-guide-cascade-complex
#1
Paul B G van Erp, Angela Patterson, Ravi Kant, Luke Berry, Sarah M Golden, Brittney L Forsman, Joshua Carter, Ryan N Jackson, Brian Bothner, Blake Wiedenheft
Bacteria and archaea rely on CRISPR (clustered regularly interspaced short palindromic repeats) RNA-guided adaptive immune systems for sequence specific elimination of foreign nucleic acids. In Escherichia coli, short CRISPR-derived RNAs (crRNAs) assemble with Cas (CRISPR-associated) proteins into a 405-kilodalton multi-subunit surveillance complex called Cascade (CRISPR-associated complex for antiviral defense). Cascade binds foreign DNA complementary to the crRNA guide and recruits Cas3, a trans-acting nuclease-helicase required for target degradation...
October 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29030428/a-retractable-lid-in-lecithin-cholesterol-acyltransferase-provides-a-structural-mechanism-for-activation-by-apolipoprotein-a-i
#2
Kelly A Manthei, Joomi Ahn, Alisa Glukhova, Wenmin Yuan, Christopher Larkin, Taylor D Manett, Louise Chang, James A Shayman, Milton J Axley, Anna Schwendeman, John J G Tesmer
Lecithin:cholesterol acyltransferase (LCAT) plays a key role in reverse cholesterol transport by transferring an acyl group from phosphatidylcholine to cholesterol, promoting the maturation of high density lipoproteins (HDL) from discoidal to spherical particles. LCAT is activated through an unknown mechanism by apolipoprotein A-I (ApoA-I) and other mimetic peptides that form a belt around HDL. Here we report the crystal structure of LCAT with an extended lid that blocks access to the active site, consistent with an inactive conformation...
October 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28993252/h-d-exchange-mass-spectrometry-and-statistical-coupling-analysis-reveal-a-role-for-allostery-in-a-ferredoxin-dependent-bifurcating-transhydrogenase-catalytic-cycle
#3
Luke Berry, Saroj Poudel, Monika Tokmina-Lukaszewska, Daniel R Colman, Diep M N Nguyen, Gerrit J Schut, Michael W W Adams, John W Peters, Eric S Boyd, Brian Bothner
Recent investigations into ferredoxin-dependent transhydrogenases, a class of enzymes responsible for electron transport, have highlighted the biological importance of flavin-based electron bifurcation (FBEB). FBEB generates biomolecules with very low reduction potential by coupling the oxidation of an electron donor with intermediate potential to the reduction of high and low potential molecules. Bifurcating systems can generate biomolecules with very low reduction potentials, such as reduced ferredoxin (Fd), from species such as NADPH...
October 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28972141/dissecting-the-molecular-assembly-of-the-toxoplasma-gondii-myoa-motility-complex
#4
Cameron J Powell, Meredith L Jenkins, Michelle L Parker, Raghavendran Ramaswamy, Anne Kelsen, David M Warshaw, Gary E Ward, John E Burke, Martin J Boulanger
Apicomplexan parasites such as Toxoplasma gondii rely on a unique form of locomotion known as gliding motility. Generating the mechanical forces to support motility are divergent class XIV myosins (MyoA) coordinated by accessory proteins known as light chains. While the importance of the MyoA-light chain complex is well established, the detailed mechanisms governing its assembly and regulation are relatively unknown. To establish a molecular blueprint of this dynamic complex, we first mapped the adjacent binding sites of light chains MLC1 and ELC1 on the MyoA neck (residues 775-818) using a combination of hydrogen-deuterium exchange mass spectrometry (HDX-MS) and isothermal titration calorimetry (ITC)...
September 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28971440/probing-conformational-dynamics-of-tau-protein-by-hydrogen-deuterium-exchange-mass-spectrometry
#5
Richard Y-C Huang, Roxana E Iacob, Sethu Sankaranarayanan, Ling Yang, Michael Ahlijanian, Li Tao, Adrienne A Tymiak, Guodong Chen
Fibrillization of the microtubule-associated protein tau has been recognized as one of the signature pathologies of the nervous system in Alzheimer's disease, progressive supranuclear palsy, and other tauopathies. The conformational transition of tau in the fibrillization process, tau monomer to soluble aggregates to fibrils in particular, remains unclear. Here we report on the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) in combination with other biochemical approaches, including Thioflavin S fluorescence measurements, enzyme-linked immunosorbent assay (ELISA), and Western blotting to understand the heparin-induced tau's fibrillization...
October 2, 2017: Journal of the American Society for Mass Spectrometry
https://www.readbyqxmd.com/read/28956290/ion-mobility-spectrometry-mass-spectrometry-coupled-with-gas-phase-hydrogen-deuterium-exchange-for-metabolomics-analyses
#6
Hossein Maleki, Ahmad K Karanji, Sandra Majuta, Megan M Maurer, Stephen J Valentine
Ion mobility spectrometry-mass spectrometry (IMS-MS) in combination with gas-phase hydrogen/deuterium exchange (HDX) and collision-induced dissociation (CID) is evaluated as an analytical method for small-molecule standard and mixture characterization. Experiments show that compound ions exhibit unique HDX reactivities that can be used to distinguish different species. Additionally, it is shown that gas-phase HDX kinetics can be exploited to provide even further distinguishing capabilities by using different partial pressures of reagent gas...
September 27, 2017: Journal of the American Society for Mass Spectrometry
https://www.readbyqxmd.com/read/28933661/suppressing-allostery-in-epitope-mapping-experiments-using-millisecond-hydrogen-deuterium-exchange-mass-spectrometry
#7
Bin Deng, Shaolong Zhu, Andrew M Macklin, Jianrong Xu, Cristina Lento, Adnan Sljoka, Derek J Wilson
Localization of the interface between the candidate antibody and its antigen target, commonly known as epitope mapping, is a critical component of the development of therapeutic monoclonal antibodies. With the recent availability of commercial automated systems, hydrogen / deuterium eXchange (HDX) is rapidly becoming the tool for mapping epitopes preferred by researchers in both industry and academia. However, this approach has a significant drawback in that it can be confounded by 'allosteric' structural and dynamic changes that result from the interaction, but occur far from the point(s) of contact...
September 21, 2017: MAbs
https://www.readbyqxmd.com/read/28933642/epitope-characterization-of-anti-jam-a-antibodies-using-orthogonal-mass-spectrometry-and-surface-plasmon-resonance-approaches
#8
Guillaume Terral, Thierry Champion, François Debaene, Olivier Colas, Maxime Bourguet, Elsa Wagner-Rousset, Nathalie Corvaia, Alain Beck, Sarah Cianferani
Junctional adhesion molecule-A (JAM-A) is an adherens and tight junction protein expressed by endothelial and epithelial cells and associated with cancer progression. We present here the extensive characterization of immune complexes involving JAM-A antigen and three monoclonal antibodies (mAbs), including hz6F4-2, a humanized version of anti-tumoral 6F4 mAb identified by a functional and proteomic approach in our laboratory. A specific workflow that combines orthogonal approaches has been designed to determine binding stoichiometries along with JAM-A epitope mapping determination at high resolution for these three mAbs...
September 21, 2017: MAbs
https://www.readbyqxmd.com/read/28901129/peptide-level-interactions-between-proteins-and-small-molecule-drug-candidates-by-two-hydrogen-deuterium-exchange-ms-based-methods-the-example-of-apolipoprotein-e3
#9
Hanliu Wang, Don L Rempel, Daryl 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...
October 17, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28864531/multiple-proteolytic-events-in-caspase-6-self-activation-impact-conformations-of-discrete-structural-regions
#10
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 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28809482/structural-dynamics-of-15-lipoxygenase-2-via-hydrogen-deuterium-exchange
#11
Kristin D 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 members of at least one subclass, the lipoxins, are able to resolve inflammation. One step in lipoxin synthesis is the oxygenation of arachidonic acid by 15-lipoxygenase (15-LOX). 15-LOX contains two domains: a Ca(2+) binding PLAT domain and a catalytic domain. 15-LOX is a soluble cytosolic protein until binding of Ca(2+) to the PLAT domain promotes translocation to the membrane surface...
September 26, 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
#12
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/28798232/conformational-characterization-of-nerve-growth-factor-%C3%AE-reveals-that-its-regulatory-pro-part-domain-stabilizes-three-loop-regions-in-its-mature-part
#13
Esben Trabjerg, Fredrik Kartberg, Søren Christensen, Kasper D Rand
Nerve growth factor-β (NGF) is essential for the correct development of the nervous system. NGF exists in both a mature form and a pro-form (proNGF). The two forms have opposing effects on neurons: NGF induces proliferation, whereas proNGF induces apoptosis via binding to a receptor complex of the common neurotrophin receptor (p75NTR) and sortilin. The 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...
October 6, 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
#14
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/28781083/kras-g12c-drug-development-discrimination-between-switch-ii-pocket-configurations-using-hydrogen-deuterium-exchange-mass-spectrometry
#15
Jia Lu, Rane A Harrison, Lianbo Li, Mei Zeng, Sudershan Gondi, David Scott, Nathanael S Gray, John R Engen, Kenneth D Westover
KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders...
September 5, 2017: Structure
https://www.readbyqxmd.com/read/28770632/an-overview-of-hydrogen-deuterium-exchange-mass-spectrometry-hdx-ms-in-drug-discovery
#16
REVIEW
Glenn R Masson, Meredith L Jenkins, John E Burke
Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a powerful methodology to study protein dynamics, protein folding, protein-protein interactions, and protein small molecule interactions. The development of novel methodologies and technical advancements in mass spectrometers has greatly expanded the accessibility and acceptance of this technique within both academia and industry. Areas covered: This review examines the theoretical basis of how amide exchange occurs, how different mass spectrometer approaches can be used for HDX-MS experiments, as well as the use of HDX-MS in drug development, specifically focusing on how HDX-MS is used to characterize bio-therapeutics, and its use in examining protein-protein and protein small molecule interactions...
October 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28770577/sec-saxs-and-hdx-ms-a-powerful-combination-the-case-of-the-calcium-binding-domain-of-a-bacterial-toxin
#17
REVIEW
Darragh P O'Brien, Sébastien Brier, Daniel Ladant, Dominique Durand, Alexandre Chenal, Patrice Vachette
Small-angle X-ray scattering (SAXS) is a relatively simple experimental technique that provides information on the global conformation of macromolecules in solution, be they fully structured, partially, or extensively unfolded. Size exclusion chromatography in line with a SAXS measuring cell considerably improves the monodispersity and ideality of solutions, the two main requirements of a "good" SAXS sample. Hydrogen/deuterium exchange monitored by mass spectrometry (HDX-MS) offers a wealth of information regarding the solvent accessibility at the local (peptide) level...
August 2, 2017: Biotechnology and Applied Biochemistry
https://www.readbyqxmd.com/read/28765527/calcium-ion-induced-structural-changes-promote-dimerization-of-secretagogin-which-is-required-for-its-insulin-secretory-function
#18
Jae-Jin Lee, Seo-Yun Yang, Jimin Park, James E Ferrell, Dong-Hae Shin, Kong-Joo Lee
Secretagogin (SCGN), a hexa EF-hand calcium binding protein, plays key roles in insulin secretion in pancreatic β-cells. It is not yet understood how the binding of Ca(2+) to human SCGN (hSCGN) promotes secretion. Here we have addressed this question, using mass spectrometry combined with a disulfide searching algorithm DBond. We found that the binding of Ca(2+) to hSCGN promotes the dimerization of hSCGN via the formation of a Cys193-Cys193 disulfide bond. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics studies revealed that Ca(2+) binding to the EF-hands of hSCGN induces significant structural changes that affect the solvent exposure of N-terminal region, and hence the redox sensitivity of the Cys193 residue...
August 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28742962/characterization-of-intramolecular-interactions-of-cytochrome-c-using-hydrogen-deuterium-exchange-trapped-ion-mobility-spectrometry-mass-spectrometry-and-molecular-dynamics
#19
Juan Camilo Molano-Arevalo, Kevin Jeanne Dit Fouque, Khoa Pham, Jaroslava Miksovska, Mark E Ridgeway, Melvin A Park, Francisco Fernandez-Lima
Globular proteins, such as cytochrome c (cyt c), display an organized native conformation, maintained by a hydrogen bond interaction network. In the present work, the structural interrogation of kinetically trapped intermediates of cyt c was performed by correlating the ion-neutral collision cross section (CCS) and charge state with the starting solution conditions and time after desolvation using collision induced activation (CIA), time-resolved hydrogen/deuterium back exchange (HDX) and trapped ion mobility spectrometry-mass spectrometry (TIMS-MS)...
September 5, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28737905/metabolism-of-t-2-toxin-in-farm-animals-and-human-in-vitro-and-in-chickens-in-vivo-using-ultra-high-performance-liquid-chromatography-quadrupole-time-of-flight-hybrid-mass-spectrometry-along-with-online-hydrogen-deuterium-exchange-technique
#20
COMPARATIVE STUDY
Shupeng Yang, Marthe De Boevre, Huiyan Zhang, Karl De Ruyck, Feifei Sun, Jinzhen Zhang, Yue Jin, Yanshen Li, Zhanhui Wang, Suxia Zhang, Jinhui Zhou, Yi Li, Sarah De Saeger
After being incubated with animal and human liver microsomes, metabolites of phase I and II were investigated. A comparison was performed by ultrahigh performance liquid chromatography-quadrupole/time-of-flight coupled to mass spectrometry (UHPLC-Q/TOF). Consequently, a total of four phase I metabolites and three glucuronide binding metabolites of T-2 toxin were discovered. Although a significant metabolic difference was observed among six species, HT-2 toxin was the major product in all species. In addition, the in vivo metabolism of T-2 toxin after oral administration was also investigated in chickens, In total, 18 metabolites were detected, of which 13 were novel, to our knowledge, and reported for the first time...
August 23, 2017: Journal of Agricultural and Food Chemistry
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