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hydrogen deuterium exchange

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https://www.readbyqxmd.com/read/28638775/host-guest-complexes-of-c-ethyl-2-methylresorcinarene-and-aromatic-n-n-dioxides
#1
Rakesh Puttreddy, Ngong Kodiah Beyeh, Robin H A Ras, Kari Rissanen
The C-ethyl-2-methylresorcinarene (1) forms 1:1 in-cavity complexes with aromatic N,N'-dioxides, only if each of the aromatic rings has an N-O group. The structurally different C-shaped 2,2'-bipyridine N,N'-dioxide (2,2'-BiPyNO) and the linear rod-shaped 4,4'-bipyridine N,N'-dioxide (4,4'-BiPyNO) both form 1:1 in-cavity complexes with the host resorcinarene in C4v crown and C2v conformations, respectively. In the solid state, the host-guest interactions between the 1,3-bis(4-pyridyl)propane N,N'-dioxide (BiPyPNO) and the host 1 stabilize the unfavorable anti-gauche conformation...
June 2017: ChemistryOpen
https://www.readbyqxmd.com/read/28634122/mapping-the-binding-interface-in-a-non-covalent-size-variant-of-a-monoclonal-antibody-using-native-mass-spectrometry-hydrogen-deuterium-exchange-mass-spectrometry-and-computational-analysis
#2
Yuetian Yan, Hui Wei, Sutjano Jusuf, Stanley R Krystek, Jie Chen, Guodong Chen, Richard T Ludwig, Li Tao, Tapan K Das
Variants of monoclonal antibody containing an extra light chain has been reported in protein products(1-3). Due to potential impact on potency and immunogenicity, it is important to understand the formation mechanism of such variants so that appropriate control strategies can be implemented to assure product quality. In a model monoclonal antibody, we observed a size variant with an extra light chain non-covalently associated with the monomer (later named as "1.2mer"). The interaction between monomer and the extra light chain was characterized by native spray and hydrogen/deuterium exchange mass spectrometry (HDX MS) techniques...
June 17, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28630467/computational-method-allowing-hydrogen-deuterium-exchange-mass-spectrometry-at-single-amide-resolution
#3
Chris Gessner, Wieland Steinchen, Sabrina Bédard, John J Skinner, Virgil L Woods, Thomas J Walsh, Gert Bange, Dionysios P Pantazatos
Hydrogen-deuterium exchange (HDX) coupled with mass spectrometry (HDXMS) is a rapid and effective method for localizing and determining protein stability and dynamics. Localization is routinely limited to a peptide resolution of 5 to 20 amino acid residues. HDXMS data can contain information beyond that needed for defining protein stability at single amide resolution. Here we present a method for extracting this information from an HDX dataset to generate a HDXMS protein stability fingerprint. High resolution (HR)-HDXMS was applied to the analysis of a model protein of a spectrin tandem repeat that exemplified an intuitive stability profile based on the linkage of two triple helical repeats connected by a helical linker...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28629860/hydrogen-deuterium-exchange-kinetics-in-%C3%AE-lactoglobulin-epicatechin-complexes-studied-by-ftir-spectroscopy
#4
Francesca Caporaletti, Marina Carbonaro, Paola Maselli, Alessandro Nucara
Hydrogen-Deuterium exchange kinetics of of β-lactoglobulin and β-lactoglobulin (-)-epicatechin solutions has been investigated through the analysis of the amide I absorption band at 1650cm(-1) in the FTIR spectrum. H-D substitution in NH amides and residues of the protein results in a slight red-shift and in intensity changes of the amide I components: either these effects have been inspected in the framework of the Principal Components Analysis methods. The present analysis allowed to unveil three H-D kinetics at the timescale of the oligomeric fluctuations of the protein...
June 16, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28628309/dissecting-orthosteric-contacts-for-a-reverse-fragment-based-ligand-design
#5
Arun Chandramohan, Nikhil Kumar Tulsian, Ganesh Srinivasan Anand
Orthosteric sites on proteins are formed typically from non-contiguous interacting sites in three dimensional space where the composite binding interaction of a biological ligand is mediated by multiple synergistic interactions of its constituent functional groups. Through these multiple interactions, ligands stabilize both the ligand binding site and the protein fold. However, relative energetic contributions of the individual contacts in these protein-ligand interactions are difficult to resolve. Deconvolution of the contributions of these various functional groups in natural inhibitors/ligand would greatly aid in iterative fragment-based drug discovery (FBDD)...
June 19, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28627884/hdx-ms-reveals-calcium-binding-properties-and-allosteric-regulation-of-downstream-regulatory-element-antagonist-modulator-dream
#6
Jun Zhang, Jing Li, Theodore A Craig, Rajiv Kumar, Michael L Gross
Downstream regulatory element antagonist modulator (DREAM) is an EF-hand Ca2+-binding protein that also binds to specific DNA sequence, downstream regulatory elements (DRE), and thereby regulates transcription in a calcium-dependent fashion. DREAM binds to DRE in the absence of Ca2+, but detaches from DRE under Ca2+ stimulation, allowing gene expression. The Ca2+-binding properties of DREAM and the consequences of the binding on protein structure are key to understanding the function of DREAM. Here we describe the application of hydrogen deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis to investigate the Ca2+ binding properties and the subsequent conformational changes of full length DREAM...
June 19, 2017: Biochemistry
https://www.readbyqxmd.com/read/28621541/expanding-the-scope-of-electrophiles-capable-of-targeting-k-ras-oncogenes
#7
Lynn M McGregor, Meredith L Jenkins, Caitlin Kerwin, John E Burke, Kevan M Shokat
There is growing interest in reversible and irreversible covalent inhibitors that target noncatalytic amino acids in target proteins. With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by expanding the types of amino acids that can be targeted by covalent inhibitors, we survey a set of electrophiles for their ability to label carboxylates. We functionalized an optimized ligand for the K-Ras switch II pocket with a set of electrophiles previously reported to react with carboxylates and characterized the ability of these compounds to react with model nucleophiles and oncogenic K-Ras proteins...
June 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28621526/orthogonal-mass-spectrometry-based-footprinting-for-epitope-mapping-and-structural-characterization-the-il-6-receptor-upon-binding-of-protein-therapeutics
#8
Ke Sherry Li, Guodong Chen, Jingjie Mo, Richard Y-C Huang, Ekaterina G Deyanova, Brett R Beno, Steve O'Neil, Adrienne A Tymiak, Michael L Gross
Higher order structure (HOS) is a crucial determinant for the biological functions and quality attributes of protein therapeutics. Mass spectrometry (MS)-based protein footprinting approaches play an important role in elucidating the relationship between protein biophysical properties and structure. Here, we describe the use of a combined method including hydrogen-deuterium exchange (HDX), fast photochemical oxidation of proteins (FPOP) and site-specific carboxyl group footprinting to investigate the HOS of protein and protein complexes...
June 16, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28615457/deconvoluting-amp-dependent-kinase-ampk-adenine-nucleotide-binding-and-sensing
#9
Xin Gu, Yan Yan, Scott J Novick, Amanda Kovich, Devrishi Goswami, Jiyuan Ke, M H Eileen Tan, Lili Wang, Xiaodan Li, Parker de Waal, Martin R Webb, Patrick R Griffin, H Eric Xu, Karsten Melcher
AMP-activated protein kinase (AMPK) is a central cellular energy sensor that adapts metabolism and growth to the energy state of the cell. AMPK senses the ratio of adenine nucleotides (adenylate energy charge) by competitive binding of AMP, ADP, and ATP to three sites (CBS1, CBS3, and CBS4) in its γ-subunit. Since these three binding sites are functionally interconnected, it remains unclear how nucleotides bind to individual sites, which nucleotides occupy each site under physiological conditions, and how binding to one site affects binding to the other sites...
June 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28611361/discovery-of-a-novel-conformational-equilibrium-in-urokinase-type-plasminogen-activator
#10
Tobias Kromann-Hansen, Eva Louise Lange, Hans Peter Sørensen, Gholamreza Hassanzadeh-Ghassabeh, Mingdong Huang, Jan K Jensen, Serge Muyldermans, Paul J Declerck, Elizabeth A Komives, Peter A Andreasen
Although trypsin-like serine proteases have flexible surface-exposed loops and are known to adopt higher and lower activity conformations, structural determinants for the different conformations have remained largely obscure. The trypsin-like serine protease, urokinase-type plasminogen activator (uPA), is central in tissue remodeling processes and also strongly implicated in tumor metastasis. We solved five X-ray crystal structures of murine uPA (muPA) in the absence and presence of allosteric molecules and/or substrate-like molecules...
June 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28599168/impurity-profiling-of-liothyronine-sodium-by-means-of-reversed-phase-hplc-high-resolution-mass-spectrometry-on-line-h-d-exchange-and-uv-vis-absorption
#11
M Ruggenthaler, J Grass, W Schuh, C G Huber, R J Reischl
For the first time, a comprehensive investigation of the impurity profile of the synthetic thyroid API (active pharmaceutical ingredient) liothyronine sodium (LT3Na) was performed by using reversed phase HPLC and advanced structural elucidation techniques including high resolution tandem mass spectrometry (HRMS/MS) and on-line hydrogen-deuterium (H/D) exchange. Overall, 39 compounds were characterized and 25 of these related substances were previously unknown to literature. The impurity classification system recently developed for the closely related API levothyroxine sodium (LT4Na) could be applied to the newly characterized liothyronine sodium impurities resulting in a wholistic thyroid API impurity classification system...
May 30, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28596009/subzero-celsius-separations-in-three-zone-temperature-controlled-hydrogen-deuterium-exchange-mass-spectrometry
#12
Thomas E Wales, Keith E Fadgen, Michael J Eggertson, John R Engen
Hydrogen deuterium exchange mass spectrometry (HDX MS) reports on the conformational landscape of proteins by monitoring the exchange between backbone amide hydrogen atoms and deuterium in the solvent. To maintain the label for analysis, quench conditions of low temperature and pH are required during the chromatography step performed after protease digestion but before mass spectrometry. Separation at 0°C is often chosen as this is the temperature where the most deuterium can be recovered without freezing of the typical water and acetonitrile mobile phases...
June 3, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28587205/conformational-flexibility-differentiates-naturally-occurring-bet-v-1-isoforms
#13
Sarina Grutsch, Julian E Fuchs, Linda Ahammer, Anna S Kamenik, Klaus R Liedl, Martin Tollinger
The protein Bet v 1 represents the main cause for allergic reactions to birch pollen in Europe and North America. Structurally homologous isoforms of Bet v 1 can have different properties regarding allergic sensitization and Th2 polarization, most likely due to differential susceptibility to proteolytic cleavage. Using NMR relaxation experiments and molecular dynamics simulations, we demonstrate that the initial proteolytic cleavage sites in two naturally occurring Bet v 1 isoforms, Bet v 1.0101 (Bet v 1a) and Bet v 1...
June 3, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28585810/structure-based-correlation-of-light-induced-histidine-reactivity-in-a-model-protein
#14
Ming Lei, Toshiro Carcelen, Benjamin T Walters, Camellia Zamiri, Cynthia Quan, Yuzhe Hu, Julie Nishihara, Holly Yip, Nicholas Woon, Taylor Zhang, Yung-Hsiang Kao, Christian Schöneich
Light is known to induce covalently linked aggregates in proteins. These aggregates can be immunogenic and are of concern for drug product development in the biotechnology industry. Histidine (His) is proposed to be a key residue in cross-link generation ( Pattison , D. I. Photochem. Photobiol. Sci. 2012 , 11 , 38 - 53 ). However, the factors that influence the reactivity of His in proteins, especially the intrinsic factors are little known. Here, we used rhDNase, which only forms His-His covalent dimers after light treatment to determine the factors that influence the light-induced reactivity of His...
June 14, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28559318/a-mechanism-for-lipid-binding-to-apoe-and-the-role-of-intrinsically-disordered-regions-coupled-to-domain-domain-interactions
#15
Carl Frieden, Hanliu Wang, Chris M W Ho
Relative to the apolipoprotein E (apoE) E3 allele of the APOE gene, apoE4 strongly increases the risk for the development of late-onset Alzheimer's disease. However, apoE4 differs from apoE3 by only a single amino acid at position 112, which is arginine in apoE4 and cysteine in apoE3. It remains unclear why apoE3 and apoE4 are functionally different. Described here is a proposal for understanding the functional differences between these two isoforms with respect to lipid binding. A mechanism is proposed that is based on the full-length monomeric structure of the protein, on hydrogen-deuterium exchange mass spectrometry data, and on the role of intrinsically disordered regions to control protein motions...
May 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28550305/dynamics-and-ligand-induced-conformational-changes-in-human-prolyl-oligopeptidase-analyzed-by-hydrogen-deuterium-exchange-mass-spectrometry
#16
Alexandra Tsirigotaki, Roos Van Elzen, Pieter Van Der Veken, Anne-Marie Lambeir, Anastassios Economou
Prolyl oligopeptidase (PREP) is conserved in many organisms across life. It is involved in numerous processes including brain function and neuropathology, that require more than its strict proteolytic role. It consists of a seven-bladed β-propeller juxtaposed to a catalytic α/β-hydrolase domain. The conformational dynamics of PREP involved in domain motions and the gating mechanism that allows substrate accessibility remain elusive. Here we used Hydrogen Deuterium eXchange Mass Spectrometry (HDX-MS) to derive the first near-residue resolution analysis of global PREP dynamics in the presence or absence of inhibitor bound in the active site...
May 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28533135/enhanced-local-disorder-in-a-clinically-elusive-von-willebrand-factor-provokes-high-affinity-platelet-clumping
#17
Alexander Tischer, Venkata R Machha, Juan P Frontroth, Maria A Brehm, Tobias Obser, Reinhard Schneppenheim, Leland Mayne, S Walter Englander, Matthew Auton
Mutation of the cysteines forming the disulfide loop of the platelet GPIbα adhesive A1 domain of von Willebrand factor (VWF) causes quantitative VWF deficiencies in the blood and von Willebrand disease. We report two cases of transient severe thrombocytopenia induced by DDAVP treatment. Cys1272Trp and Cys1458Tyr mutations identified by genetic sequencing implicate an abnormal gain-of-function phenotype, evidenced by thrombocytopenia, which quickly relapses back to normal platelet counts and deficient plasma VWF...
May 19, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28515318/molecular-mechanism-of-activation-of-class-ia-phosphoinositide-3-kinases-pi3ks-by-membrane-localized-hras
#18
Braden D Siempelkamp, Manoj K Rathinaswamy, Meredith L Jenkins, John E Burke
Class IA PI3Ks are involved in the generation of the key lipid signaling molecule phosphatidylinositol 3,4,5-trisphosphate (PIP3), and inappropriate activation of this pathway is implicated in a multitude of human diseases, including cancer, inflammation, and primary immunodeficiencies. Class IA PI3Ks are activated downstream of the Ras superfamily of GTPases, and Ras-PI3K interaction plays a key role in promoting tumor formation and maintenance in Ras-driven tumors. Investigating the detailed molecular events in the Ras-PI3K interaction has been challenging because it occurs on a membrane surface...
May 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28514451/structure-of-the-full-length-glucagon-class-b-g-protein-coupled-receptor
#19
Haonan Zhang, Anna Qiao, Dehua Yang, Linlin Yang, Antao Dai, Chris de Graaf, Steffen Reedtz-Runge, Venkatasubramanian Dharmarajan, Hui Zhang, Gye Won Han, Thomas D Grant, Raymond G Sierra, Uwe Weierstall, Garrett Nelson, Wei Liu, Yanhong Wu, Limin Ma, Xiaoqing Cai, Guangyao Lin, Xiaoai Wu, Zhi Geng, Yuhui Dong, Gaojie Song, Patrick R Griffin, Jesper Lau, Vadim Cherezov, Huaiyu Yang, Michael A Hanson, Raymond C Stevens, Qiang Zhao, Hualiang Jiang, Ming-Wei Wang, Beili Wu
The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain...
June 8, 2017: Nature
https://www.readbyqxmd.com/read/28513578/crystal-structure-of-a-multi-domain-human-smoothened-receptor-in-complex-with-a-super-stabilizing-ligand
#20
Xianjun Zhang, Fei Zhao, Yiran Wu, Jun Yang, Gye Won Han, Suwen Zhao, Andrii Ishchenko, Lintao Ye, Xi Lin, Kang Ding, Venkatasubramanian Dharmarajan, Patrick R Griffin, Cornelius Gati, Garrett Nelson, Mark S Hunter, Michael A Hanson, Vadim Cherezov, Raymond C Stevens, Wenfu Tan, Houchao Tao, Fei Xu
The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC114, using an X-ray free-electron laser source at 2.9 Å. The structure reveals a precise arrangement of three distinct domains: a seven-transmembrane helices domain (TMD), a hinge domain (HD) and an intact extracellular cysteine-rich domain (CRD)...
May 17, 2017: Nature Communications
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