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https://www.readbyqxmd.com/read/28933661/suppressing-allostery-in-epitope-mapping-experiments-using-millisecond-hydrogen-deuterium-exchange-mass-spectrometry
#1
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/28926154/brain-functional-connectome-abnormalities-in-als-are-associated-with-disability-and-cortical-hyperexcitability
#2
Nimeshan Geevasinga, Mayuresh S Korgaonkar, Parvathi Menon, Mehdi Van den Bos, Lavier Gomes, Sheryl Foster, Matthew C Kiernan, Steve Vucic
OBJECTIVE: The present study utilized a multimodality approach encompassing connectome network combined with brain volume analysis, and assessment of cortical excitability to provide novel insights into amyotrophic lateral sclerosis (ALS) pathogenesis. METHODS: Magnetic resonance images (MRI) were acquired using a 3.0 Tesla GE Signa HDx scanner, using an 8-channel head coil. MR images for the resting state scan were acquired using echo planar imaging MR sequence, acquiring 40 contiguous axial/oblique slices...
September 19, 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/28910802/effects-of-expanded-hemodialysis-therapy-on-clinical-outcomes
#3
Sandip Mitra, Kunaal Kharbanda
The invention of dialysis has been a phenomenal advance in the treatment of kidney failure. The introduction of artificial kidneys in clinical care remains one of the most successful lifesaving interventions in modern medicine. Its glory, however, has been tempered by poor long-term outcomes and a negative qualitative impact on the lives of patients who suffer from an extremely complex, burdensome, and restricted life on dialysis. There remains a huge gap in patient well-being and outcomes between artificial kidney treatments and kidney transplantation...
2017: Contributions to Nephrology
https://www.readbyqxmd.com/read/28910798/expanded-hemodialysis-therapy-prescription-and-delivery
#4
Nils Heyne
Expanded hemodialysis (HDx) therapy is a novel treatment concept in hemodialysis patients, using innovative membrane technology with a high retention onset for improved solute clearance in the upper middle molecular range. HDx therapy thereby resolves a key limitation of current hemodialysis techniques and targets an important pathophysiologic link to many of the sequelae of end-stage renal disease. The present chapter reviews the current evidence and discusses considerations for prescription and delivery of HDx therapy upon implementation in clinical practice...
2017: Contributions to Nephrology
https://www.readbyqxmd.com/read/28910797/the-rationale-for-expanded-hemodialysis-therapy-hdx
#5
Colin A Hutchison, Martin Wolley
As dialysis membrane technologies have advanced, the ability to clear increasing numbers of uremic toxins has occurred. To date, however, the class of uremic toxins known as large middle-molecules has been classified as "difficult to remove." Expanded hemodialysis utilizes a new generation of high-retention-onset hemodialysis membranes; these membranes provide the ability to remove large middle-molecules effectively for the first time, without significant albumin loss. In this review, we evaluate the removal of large middle-molecules by the new high-retention-onset membranes, the clinical relevance of these molecules, and how expanded hemodialysis can be prescribed...
2017: Contributions to Nephrology
https://www.readbyqxmd.com/read/28910791/inflammation-and-protein-energy-wasting-in-the-uremic-milieu
#6
Magdalena Jankowska, Gabriela Cobo, Bengt Lindholm, Peter Stenvinkel
Inflammation is normally a protective and physiological response to harmful stimuli, but typically becomes an uncontrolled, maladaptive, and persistent process in patients with end-stage renal disease (ESRD). Through a deleterious cascade of poorly controlled reactions mediated by biologically active molecules (also called middle molecular weight uremia retention solutes), inflammation associates with a range of complications including cardiovascular disease and protein-energy wasting (PEW). Persistent inflammation, which is central to the conceptual etiological models of PEW and the malnutrition, inflammation, and atherosclerosis syndrome, induces and reignites processes leading to PEW in a number of ways including stimulation of both direct and indirect mechanisms of muscle proteolysis...
2017: Contributions to Nephrology
https://www.readbyqxmd.com/read/28910786/the-evolving-patterns-of-uremia-unmet-clinical-needs-in-dialysis
#7
Xueqing Yu
End-stage renal disease (ESRD) has become a challenging health problem worldwide. Currently, ESRD patients treated with hemodialysis mainly undergo low-flux hemodialysis, high-flux hemodialysis (HF-HD), or hemodiafiltration (HDF). The clearance of middle and large molecules is, however, quite insufficient as regards HF-HD, HDF, and on-line HDF. An unsatisfactory prognosis has led to improved dialysis technology and materials; both protein-leaking membranes and high cut-off membranes increase the clearance of uremic toxin, but in clinical application they may induce albumin loss...
2017: Contributions to Nephrology
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
#8
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/28890360/synergistic-regulation-of-coregulator-nuclear-receptor-interaction-by-ligand-and-dna
#9
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/28877504/remodeling-kras
#10
Daniel J Deredge, Patrick L Wintrode
Mutations in members of the RAS family of small GTPases have been associated with numerous human cancers. However, RAS family members are notoriously difficult to target. In this issue of Structure, Lu et al. (2017) examine the effects of two compounds with distinct chemical scaffolds on the structure and dynamics of an oncogenic KRAS mutant, thus highlighting the usefulness of HDX-MS for drug development.
September 5, 2017: Structure
https://www.readbyqxmd.com/read/28821744/exploring-the-sequence-based-prediction-of-folding-initiation-sites-in-proteins
#11
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
#12
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
#13
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
#14
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/28797100/mapping-the-contact-surfaces-in-the-lamin-a-aimp3-complex-by-hydrogen-deuterium-exchange-ft-icr-mass-spectrometry
#15
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
#16
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
#17
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
#18
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 mono-dispersity 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
#19
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/28758397/calcium-mediated-control-of-s100-proteins-allosteric-communication-via-an-agitator-signal-blocking-mechanism
#20
Yiming Xiao, Gary S Shaw, Lars Konermann
Allosteric proteins possess dynamically coupled residues for the propagation of input signals to distant target binding sites. The input signals usually correspond to "effector is present" or "effector is not present". Many aspects of allosteric regulation remain incompletely understood. This work focused on S100A11, a dimeric EF-hand protein with two hydrophobic target binding sites. An annexin peptide (Ax) served as the target. Target binding is allosterically controlled by Ca(2+) over a distance of ∼26 Å...
August 14, 2017: Journal of the American Chemical Society
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