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https://www.readbyqxmd.com/read/28813004/lactose-binding-induces-opposing-dynamics-changes-in-human-galectins-revealed-by-nmr-based-hydrogen-deuterium-exchange
#1
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
#2
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
#3
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 14, 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
#4
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
#5
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...
July 25, 2017: Structure
https://www.readbyqxmd.com/read/28770632/an-overview-of-hydrogen-deuterium-exchange-mass-spectrometry-hdx-ms-in-drug-discovery
#6
Glenn R Masson, Meredith L Jenkins, John E Burke
Introduction- 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...
August 3, 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
#7
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
#8
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
#9
Yiming Xiao, Gary Stephen 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 target. Target binding is allosterically controlled by Ca2+ over a distance of ~26 Å. Ca2+ promotes formation of a [Ca4 S100 Ax2] complex, where the Ax peptides are accommodated between helices III/IV and III'/IV'...
July 31, 2017: Journal of the American Chemical Society
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
#10
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)...
August 11, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28727449/use-of-maldi-ms-combined-with-differential-hydrogen-deuterium-exchange-for-semiautomated-protein-global-conformational-screening
#11
Gregory F Pirrone, Heather Wang, Nicole Canfield, Alexander S Chin, Timothy A Rhodes, Alexey A Makarov
Matrix-assisted laser desorption/ionization (MALDI) coupled with a time-of-flight (TOF) mass-spectrometry (MS) detector is acknowledged to be very useful for analysis of biological molecules. At the same time, hydrogen-deuterium exchange (HDX) is a well-known technique for studying protein higher-order structure. However, coupling MALDI with HDX has been challenging because of undesired back-exchange reactions during analysis. In this report, we survey an approach that utilizes MALDI coupled with an automated sample preparation to compare global conformational changes of proteins under different solution conditions using differential HDX...
August 4, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28724631/the-axl-kinase-domain-in-complex-with-a-macrocyclic-inhibitor-offers-first-structural-insights-into-an-active-tam-receptor-kinase
#12
Ketan S Gajiwala, Neil Grodsky, Ben Bolaños, Junli Feng, RoseAnn Ferre, Sergei Timofeevski, Meirong Xu, Brion W Murray, Ted W Johnson, Al Stewart
The receptor tyrosine kinase (RTK) family consisting of Tyro3, Axl and Mer (TAM) is one of the most recently identified RTK families. TAM receptors are upregulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination...
July 19, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28702519/bottom-up-hydrogen-deuterium-exchange-mass-spectrometry-data-analysis-and-interpretation
#13
Kerene A Brown, Derek J Wilson
Hydrogen Deuterium Exchange (HDX) Mass Spectrometry (MS) is a sensitive analytical technique that provides information on protein conformation and dynamics in solution. It is commonly used in the study of protein-ligand and protein-protein interactions and more recently in the pharmaceutical industry for epitope mapping, screening drug candidates and in the comparison of biopharmaceuticals to biosimilars. HDX-MS monitors the exchange of protein backbone hydrogen atoms with deuterium in solution. Recent advancements in HDX automation and data analysis, have taken the emphasis off developing a fundamental understanding of HDX, which is still lacking...
August 7, 2017: Analyst
https://www.readbyqxmd.com/read/28700824/application-of-hydrogen-deuterium-exchange-mass-spectrometry-to-biopharmaceutical-development-requirements-improved-sensitivity-to-detection-of-conformational-changes
#14
Lea Bonnington, Ingo Lindner, Ulrich Gilles, Tobias Kailich, Dietmar Reusch, Patrick Bulau
The usefulness of the higher-order structure information provided by hydrogen/deuterium exchange mass spectrometry (HDX-MS) in the protein therapeutic field is undisputed; however, its applicability as a method for critical quality and comparability assessment has until now not been demonstrated. Here we present results demonstrating for the first time the applicability of the HDX-MS technique to monitor structural changes due to methionine oxidation at sensitivity levels realistic to the requirements of biopharmaceutical research and development...
July 28, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28696098/enhanced-binding-affinity-via-destabilization-of-the-unbound-state-a-millisecond-hydrogen-deuterium-exchange-study-of-the-interaction-between-p53-and-a-pleckstrin-homology-domain
#15
Shaolong Zhu, Rahima Khatun, Cristina Lento, Yi Sheng, Derek J Wilson
The incorporation of intrinsically disordered domains enables proteins to engage a wide variety of targets, with phosphorylation often modulating target specificity and affinity. Although phosphorylation can clearly act as a chemical driver of complexation in structured proteins, e.g., by abrogating or permitting new charge-charge interactions, the basis for enhancement of the hydrophobically driven interactions that are typical of disordered protein-target complexation is less clear. To determine how phosphorylation can positively impact target recruitment in disordered domains, we have examined the interaction between the disordered N-terminal transactivation domain (TAD) of p53 and the pleckstrin homology (PH) domain of p62...
July 19, 2017: Biochemistry
https://www.readbyqxmd.com/read/28692141/a-discontinuous-autoinhibitory-module-masks-the-a1-domain-of-von-willebrand-factor
#16
Wei Deng, Yingchun Wang, Samuel A Druzak, John F Healey, Anum K Syed, Pete Lollar, Renhao Li
BACKGROUND: How von Willebrand factor (VWF) senses and responds to shear flow remains unclear. In the absence of shear VWF or its fragments can be induced to bind spontaneously to platelet GPIbα. Objectives To elucidate the auto-inhibition mechanism of VWF. METHODS: Hydrogen-deuterium exchange (HDX) of two recombinant VWF fragments expressed from baby hamster kidney cells were measured and compared. RESULTS: The shortA1 protein contains VWF residues 1261-1472 and binds GPIbα with a significantly higher affinity than the longA1 protein that contains VWF residues 1238-1472...
July 10, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28676225/identification-of-cytidine-5-triphosphate-synthase1-selective-inhibitory-peptide-from-random-peptide-library-displayed-on-t7-phage
#17
Kotaro Sakamoto, Yoshihiro Ishibashi, Ryutaro Adachi, Shin-Ichi Matsumoto, Hideyuki Oki, Yusuke Kamada, Satoshi Sogabe, Yumi Zama, Jun-Ichi Sakamoto, Akiyoshi Tani
Cytidine triphosphate synthase 1 (CTPS1) is an enzyme expressed in activated lymphocytes that catalyzes the conversion of uridine triphosphate (UTP) to cytidine triphosphate (CTP) with ATP-dependent amination, using either L-glutamine or ammonia as the nitrogen source. Since CTP plays an important role in DNA/RNA synthesis, phospholipid synthesis, and protein sialyation, CTPS1-inhibition is expected to control lymphocyte proliferation and size expansion in inflammatory diseases. In contrast, CTPS2, an isozyme of CTPS1 possessing 74% amino acid sequence homology, is expressed in normal lymphocytes...
July 1, 2017: Peptides
https://www.readbyqxmd.com/read/28671821/the-t-cell-receptor-can-bind-to-the-peptide-bound-major-histocompatibility-complex-and-uncomplexed-%C3%AE-2-microglobulin-through-distinct-binding-sites
#18
Patrick S Merkle, Melita Irving, Song Hongjian, Mathias Ferber, Thomas J D Jørgensen, Kirsten Scholten, Immanuel Luescher, George Coukos, Vincent Zoete, Michel A Cuendet, Olivier Michielin, Kasper D Rand
T-Cell receptor (TCR)-mediated recognition of the peptide-bound major histocompatibility complex (pMHC) initiates an adaptive immune response against antigen-presenting target cells. The recognition events take place at the TCR-pMHC interface, and their effects on TCR conformation and dynamics are controversial. Here, we have measured the time-resolved hydrogen/deuterium exchange (HDX) of a soluble TCR in the presence and absence of its cognate pMHC by mass spectrometry to delineate the impact of pMHC binding on solution-phase structural dynamics in the TCR...
August 1, 2017: Biochemistry
https://www.readbyqxmd.com/read/28657298/aspergillus-niger-prolyl-endoprotease-for-hydrogen-deuterium-exchange-mass-spectrometry-and-protein-structural-studies
#19
Liana Tsiatsiani, Michiel Akeroyd, Maurien Olsthoorn, Albert J R Heck
To monitor the structural integrity of therapeutic proteins, hydrogen-deuterium exchange mass spectrometry (HDX-MS) is increasingly utilized in the pharmaceutical industry. The successful outcome of HDX-MS analyses depends on the sample preparation conditions, which involve the rapid digestion of proteins at 0 °C and pH 2.5. Very few proteases are able to withstand such harsh conditions, with pepsin being the best-known exception, even though its activity is also strongly reduced at 0 °C. Here, we evaluate the usage of a prolyl endopeptidase from Aspergillus niger (An-PEP) for HDX-MS...
August 1, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28652337/mine-conformational-dynamics-regulate-membrane-binding-mind-interaction-and-min-oscillation
#20
Kyung-Tae Park, Maria T Villar, Antonio Artigues, Joe Lutkenhaus
In Escherichia coli MinE induces MinC/MinD to oscillate between the ends of the cell, contributing to the precise placement of the Z ring at midcell. To do this, MinE undergoes a remarkable conformational change from a latent 6β-stranded form that diffuses in the cytoplasm to an active 4β-stranded form bound to the membrane and MinD. How this conformational switch occurs is not known. Here, using hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS) we rule out a model in which the two forms are in rapid equilibrium...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
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