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https://www.readbyqxmd.com/read/29336549/top-down-hydrogen-deuterium-exchange-analysis-of-protein-structures-using-ultraviolet-photodissociation-uvpd
#1
Nicholas I Brodie, Romain Huguet, Terry Zhang, Rosa Viner, Vlad Zabrouskov, Jingxi Pan, Evgeniy V Petrotchenko, Christoph H Borchers
Top-down hydrogen-deuterium exchange (HDX) analysis using electron capture or transfer dissociation Fourier transform mass spectrometry is a powerful method for the analysis of secondary structure of proteins in solution. The resolution of the method is a function of the extensive fragmentation of backbone bonds in the proteins. While fragmentation is usually extensive near the N- and C-termini, electron capture (ECD) or electron transfer dissociation (ETD) fragmentation methods sometimes lack good coverage of certain regions of the protein - most often in the middle of the sequence...
January 16, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29329326/utilization-of-peptide-phage-display-to-investigate-hotspots-on-il-17a-and-what-it-means-for-drug-discovery
#2
Joey P Ting, Frances Tung, Stephen Antonysamy, Stephen Wasserman, Spencer B Jones, Feiyu F Zhang, Alfonso Espada, Howard Broughton, Michael J Chalmers, Michael E Woodman, Holly A Bina, Jeffrey A Dodge, Jordi Benach, Aiping Zhang, Christopher Groshong, Danalyn Manglicmot, Marijane Russell, Sepideh Afshar
To date, IL-17A antibodies remain the only therapeutic approach to correct the abnormal activation of the IL-17A/IL-17R signaling complex. Why is it that despite the remarkable success of IL-17 antibodies, there is no small molecule antagonist of IL-17A in the clinic? Here we offer a unique approach to address this question. In order to understand the interaction of IL-17A with its receptor, we combined peptide discovery using phage display with HDX, crystallography, and functional assays to map and characterize hot regions that contribute to most of the energetics of the IL-17A/IL-17R interaction...
2018: PloS One
https://www.readbyqxmd.com/read/29327743/the-unexpected-racemization-and-hydrogen-deuterium-exchange-of-the-hydrogen-at-the-%C3%AE-carbon-of-proline-analogs-containing-the-5-azoniaspiro-4-4-nonyl-group
#3
B Setner, M Wierzbicka, L Jerzykiewicz, M Lisowski, Z Szewczuk
Recently, we developed a novel non-fragmenting quaternary ammonium ionization tag for the mass spectrometric sensitive sequencing of peptides, based on the N-spiro proline residue (5-azoniaspiro[4.4.]nonyl-carbonyl). Herein, we present an unexpected racemization and the hydrogen-deuterium exchange (HDX) at the α-C atom of the proline derivative under basic aqueous conditions (1% water solution of triethylamine). The deuterium atom, substituted for the α-C atom, does not undergo back-exchange under acidic aqueous conditions which makes the deuterated isotopologue a promising stabile isotope-coded internal standard for quantitative analysis by mass spectrometry...
January 12, 2018: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29299838/optimization-of-feasibility-stage-for-hydrogen-deuterium-exchange-mass-spectrometry
#4
Yoshitomo Hamuro, Stephen J Coales
The practice of HDX-MS remains somewhat difficult, not only for newcomers but also for veterans, despite its increasing popularity. While a typical HDX-MS project starts with a feasibility stage where the experimental conditions are optimized and the peptide map is generated prior to the HDX study stage, the literature usually reports only the HDX study stage. In this protocol, we describe a few considerations for the initial feasibility stage, more specifically, how to optimize quench conditions, how to tackle the carryover issue, and how to apply the pepsin specificity rule...
January 3, 2018: Journal of the American Society for Mass Spectrometry
https://www.readbyqxmd.com/read/29287065/calmodulin-fishing-with-a-structurally-disordered-bait-triggers-cyaa-catalysis
#5
Darragh P O'Brien, Dominique Durand, Alexis Voegele, Véronique Hourdel, Marilyne Davi, Julia Chamot-Rooke, Patrice Vachette, Sébastien Brier, Daniel Ladant, Alexandre Chenal
Once translocated into the cytosol of target cells, the catalytic domain (AC) of the adenylate cyclase toxin (CyaA), a major virulence factor of Bordetella pertussis, is potently activated by binding calmodulin (CaM) to produce supraphysiological levels of cAMP, inducing cell death. Using a combination of small-angle X-ray scattering (SAXS), hydrogen/deuterium exchange mass spectrometry (HDX-MS), and synchrotron radiation circular dichroism (SR-CD), we show that, in the absence of CaM, AC exhibits significant structural disorder, and a 75-residue-long stretch within AC undergoes a disorder-to-order transition upon CaM binding...
December 29, 2017: PLoS Biology
https://www.readbyqxmd.com/read/29239690/antibody-drug-conjugates-design-and-development-for-therapy-and-imaging-in-and-beyond-cancer-labex-mabimprove-industrial-workshop-july-27-28-2017-tours-france
#6
Camille Martin, Claire Kizlik-Masson, André Pèlegrin, Hervé Watier, Marie-Claude Viaud-Massuard, Nicolas Joubert
The annual "Antibody Industrial Symposium", co organized by LabEx MAbImprove, MabDesign and Polepharma, was held in Tours, France on June 27-28, 2017. The focus was on antibody-drug-conjugates (ADCs), new entities which realize the hope of Paul Ehrlich's magic bullet. ADCs result from the bioconjugation of a highly cytotoxic drug to a selective monoclonal antibody, which acts as a vector. Building on knowledge gained during the development of three approved ADCs, brentuximab vedotin (Adcetris®), ado trastuzumab emtansine (Kadcyla®) and inotuzumab ozogamicin (Besponsa®), and the many ADCs in development, this meeting addressed strategies and the latest innovations in the field from fundamental research to manufacturing...
December 14, 2017: MAbs
https://www.readbyqxmd.com/read/29196701/the-repeat-region-of-cortactin-is-intrinsically-disordered-in-solution
#7
Xiaofeng Li, Yeqing Tao, James W Murphy, Alexander N Scherer, TuKiet T Lam, Alan G Marshall, Anthony J Koleske, Titus J Boggon
The multi-domain protein, cortactin, contains a 37-residue repeating motif that binds to actin filaments. This cortactin repeat region comprises 6½ similar copies of the motif and binds actin filaments. To better understand this region of cortactin, and its fold, we conducted extensive biophysical analysis. Size exclusion chromatography with multi-angle light scattering (SEC-MALS) reveals that neither constructs of the cortactin repeats alone or together with the adjacent helical region homo-oligomerize. Using circular dichroism (CD) we find that in solution the cortactin repeats resemble a coil-like intrinsically disordered protein...
December 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29190734/a-novel-porphyromonas-gingivalis-enzyme-an-atypical-dipeptidyl-peptidase-iii-with-an-arm-repeat-domain
#8
Altijana Hromić-Jahjefendić, Nina Jajčanin Jozić, Saša Kazazić, Marina Grabar Branilović, Zrinka Karačić, Jörg H Schrittwieser, Krishna Mohan Padmanabha Das, Marko Tomin, Monika Oberer, Karl Gruber, Marija Abramić, Sanja Tomić
Porphyromonas gingivalis, an asaccharolytic Gram-negative oral anaerobe, is a major pathogen associated with adult periodontitis, a chronic infective disease that a significant percentage of the human population suffers from. It preferentially utilizes dipeptides as its carbon source, suggesting the importance of dipeptidyl peptidase (DPP) types of enzyme for its growth. Until now DPP IV, DPP5, 7 and 11 have been extensively investigated. Here, we report the characterization of DPP III using molecular biology, biochemical, biophysical and computational chemistry methods...
2017: PloS One
https://www.readbyqxmd.com/read/29185984/conserved-rna-binding-specificity-of-polycomb-repressive-complex-2-is-achieved-by-dispersed-amino-acid-patches-in-ezh2
#9
Yicheng Long, Ben Bolanos, Lihu Gong, Wei Liu, Karen J Goodrich, Xin Yang, Siming Chen, Anne R Gooding, Karen A Maegley, Ketan S Gajiwala, Alexei Brooun, Thomas R Cech, Xin Liu
Polycomb repressive complex 2 (PRC2) is a key chromatin modifier responsible for methylation of lysine 27 in histone H3. PRC2 has been shown to interact with thousands of RNA species in vivo, but understanding the physiological function of RNA binding has been hampered by the lack of separation-of-function mutants. Here, we use comprehensive mutagenesis and hydrogen deuterium exchange mass spectrometry (HDX-MS) to identify critical residues for RNA interaction in PRC2 core complexes from Homo sapiens and Chaetomium thermophilum, for which crystal structures are known...
November 29, 2017: ELife
https://www.readbyqxmd.com/read/29181875/integration-of-routine-qa-data-into-mega-analysis-may-improve-quality-and-sensitivity-of-multisite-diffusion-tensor-imaging-studies
#10
Peter Kochunov, Erin W Dickie, Joseph D Viviano, Jessica Turner, Peter B Kingsley, Neda Jahanshad, Paul M Thompson, Meghann C Ryan, Els Fieremans, Dmitry Novikov, Jelle Veraart, Elliot L Hong, Anil K Malhotra, Robert W Buchanan, Sofia Chavez, Aristotle N Voineskos
A novel mega-analytical approach that reduced methodological variance was evaluated using a multisite diffusion tensor imaging (DTI) fractional anisotropy (FA) data by comparing white matter integrity in people with schizophrenia to controls. Methodological variance was reduced through regression of variance captured from quality assurance (QA) and by using Marchenko-Pastur Principal Component Analysis (MP-PCA) denoising. N = 192 (119 patients/73 controls) data sets were collected at three sites equipped with 3T MRI systems: GE MR750, GE HDx, and Siemens Trio...
November 27, 2017: Human Brain Mapping
https://www.readbyqxmd.com/read/29166011/a-cooperative-folding-unit-as-the-structural-link-for-energetic-coupling-within-a-protein
#11
Nathan W Gardner, Sarah M McGinness, Jainik Panchal, Elizabeth M Topp, Chiwook Park
Previously, we demonstrated that ligand binding to Escherichia coli cofactor-dependent phosphoglycerate mutase (dPGM), a homodimeric protein, is energetically coupled with dimerization. The equilibrium unfolding of dPGM occurs with a stable, monomeric intermediate. Binding of several non-substrate metabolites stabilizes the dimeric native form over the monomeric intermediate, reducing the population of the intermediate. Both the active site and the dimer interface appear to be unfolded in the intermediate. We hypothesized that a loop containing residues 118-152 was responsible for the energetic coupling between the dimer interface and the distal active site and was unfolded in the intermediate...
November 22, 2017: Biochemistry
https://www.readbyqxmd.com/read/29155349/endogenous-sulfur-dioxide-regulates-hippocampal-neuron-apoptosis-in-developing-epileptic-rats-and-is-associated-with-the-perk-signaling-pathway
#12
Manman Niu, Ying Han, Qinrui Li, Jing Zhang
Epilepsy is among the most common neurological diseases in children. Recurrent seizures can result in hippocampal damage and seriously impair learning and memory functions in children. However, the mechanisms underlying epilepsy-related brain injury are unclear. Neuronal apoptosis is among the most common neuropathological manifestations of brain injury. Endogenous sulfur dioxide (SO2) has been shown to be involved in seizures and related neuron apoptosis. However, the role of endogenous SO2 in epilepsy remains unclear...
November 16, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29151349/changes-in-enzyme-structural-dynamics-studied-by-hydrogen-exchange-mass-spectrometry-ligand-binding-effects-or-catalytically-relevant-motions
#13
Courtney S Fast, Siavash Vahidi, Lars Konermann
It is believed that enzyme catalysis is facilitated by conformational dynamics of the protein scaffold that surrounds the active site. Yet, the exact nature of catalytically relevant protein motions remains largely unknown. Hydrogen/deuterium exchange (HDX) mass spectrometry (MS) reports on backbone H-bond fluctuations. HDX/MS therefore represents a promising avenue for probing the relationship between enzyme dynamics and catalysis. A seemingly straightforward strategy for such measurements involves comparative measurements during substrate turnover and in the resting state...
November 18, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29150441/co-ii-and-ni-ii-binding-of-the-escherichia-coli-transcriptional-repressor-rcnr-orders-its-n-terminus-alters-helix-dynamics-and-reduces-dna-affinity
#14
Hsin-Ting Huang, Cedric E Bobst, Jeffrey S Iwig, Peter T Chivers, Igor A Kaltashov, Michael J Maroney
RcnR, a transcriptional regulator in Escherichia coli, derepresses the expression of the export proteins RcnAB upon binding Ni(II) or Co(II). Lack of structural information has precluded elucidation of the allosteric basis for the decreased DNA affinity in RcnR's metal-bound states. Here, using hydrogen-deuterium exchange coupled with MS (HDX-MS), we probed the RcnR structure in the presence of DNA, the cognate metal ions Ni(II) and Co(II), or the noncognate metal ion Zn(II). We found that cognate metal binding altered the flexibility from the N-terminus through helix 1 and modulated the RcnR-DNA interaction...
November 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29138428/structural-disorder-and-induced-folding-within-two-cereal-aba-stress-and-ripening-asr-proteins
#15
Karama Hamdi, Edoardo Salladini, Darragh P O'Brien, Sébastien Brier, Alexandre Chenal, Ines Yacoubi, Sonia Longhi
Abscisic acid (ABA), stress and ripening (ASR) proteins are plant-specific proteins involved in plant response to multiple abiotic stresses. We previously isolated the ASR genes and cDNAs from durum wheat (TtASR1) and barley (HvASR1). Here, we show that HvASR1 and TtASR1 are consistently predicted to be disordered and further confirm this experimentally. Addition of glycerol, which mimics dehydration, triggers a gain of structure in both proteins. Limited proteolysis showed that they are highly sensitive to protease degradation...
November 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29135326/hydrogen-deuterium-exchange-mass-spectrometry-and-computational-modeling-reveal-a-discontinuous-epitope-of-an-antibody-tl1a-interaction
#16
Richard Y-C Huang, Stanley R Krystek, Nathan Felix, Robert F Graziano, Mohan Srinivasan, Achal Pashine, Guodong Chen
TL1A, a tumor necrosis factor-like cytokine, is a ligand for the death domain receptor DR3. TL1A, upon binding to DR3, can stimulate lymphocytes and trigger secretion of proinflammatory cytokines. Therefore, blockade of TL1A/DR3 interaction may be a potential therapeutic strategy for autoimmune and inflammatory diseases. Recently, the anti-TL1A monoclonal antibody 1 (mAb1) with a strong potency in blocking the TL1A/DR3 interaction was identified. Here, we report on the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) to obtain molecular-level details of mAb1's binding epitope on TL1A...
November 14, 2017: MAbs
https://www.readbyqxmd.com/read/29131142/a-consensus-model-of-human-apolipoprotein-a-i-in-its-monomeric-and-lipid-free-state
#17
John T Melchior, Ryan G Walker, Allison L Cooke, Jamie Morris, Mark Castleberry, Thomas B Thompson, Martin K Jones, Hyun D Song, Kerry-Anne Rye, Michael N Oda, Mary G Sorci-Thomas, Michael J Thomas, Jay W Heinecke, Xiaohu Mei, David Atkinson, Jere P Segrest, Sissel Lund-Katz, Michael C Phillips, W Sean Davidson
Apolipoprotein (apo)A-I is an organizing scaffold protein that is critical to high-density lipoprotein (HDL) structure and metabolism, probably mediating many of its cardioprotective properties. However, HDL biogenesis is poorly understood, as lipid-free apoA-I has been notoriously resistant to high-resolution structural study. Published models from low-resolution techniques share certain features but vary considerably in shape and secondary structure. To tackle this central issue in lipoprotein biology, we assembled a team of structural biologists specializing in apolipoproteins and set out to build a consensus model of monomeric lipid-free human apoA-I...
November 13, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29129068/structural-and-functional-characterization-of-a-hole-hole-homodimer-variant-in-a-knob-into-hole-bispecific-antibody
#18
Hui-Min Zhang, Charlene Li, Ming Lei, Victor Lundin, Ho Young Lee, Milady Ninonuevo, Kevin Lin, Guanghui Han, Wendy Sandoval, Dongsheng Lei, Gang Ren, Jennifer Zhang, Hongbin Liu
Bispecific antibodies have great potential to be the next-generation biotherapeutics due to their ability to simultaneously recognize two different targets. Compared to conventional monoclonal antibodies, knob-into-hole bispecific antibodies face unique challenges in production and characterization due to the increase in variant possibilities, such as homodimerization in covalent and non-covalent forms. In this study, a storage- and pH-sensitive hydrophobic interaction chromatography (HIC) profile change was observed for the hole-hole homodimer, and the multiple HIC peaks were explored and shown to be conformational isomers...
November 12, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29092908/coordination-and-redox-state-dependent-structural-changes-of-the-heme-based-oxygen-sensor-afgchk-associated-with-intraprotein-signal-transduction
#19
Martin Stranava, Petr Man, Tereza Skalova, Petr Kolenko, Jan Blaha, Veronika Fojtikova, Vaclav Martinek, Jan Dohnalek, Alzbeta Lengalova, Michal Rosulek, Toru Shimizu, Marketa Martinkova
The heme-based oxygen sensor histidine kinase AfGcHK is part of a two-component signal transduction system in bacteria. O2 binding to the Fe(II) heme complex of its N-terminal globin domain strongly stimulates autophosphorylation at His-183 in its C-terminal kinase domain. The 6-coordinate heme Fe(III)-OH- and -CN- complexes of AfGcHK are also active, but the 5-coordinate heme Fe(II) complex and the heme-free apo-form are inactive. Here, we determined the crystal structures of the isolated dimeric globin domains of the active Fe(III)-CN- and inactive 5-coordinate Fe(II) forms, revealing striking structural differences on the heme-proximal side of the globin domain...
November 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29080206/structural-dynamics-of-the-gw182-silencing-domain-including-its-rna-recognition-motif-rrm-revealed-by-hydrogen-deuterium-exchange-mass-spectrometry
#20
Maja K Cieplak-Rotowska, Krzysztof Tarnowski, Marcin Rubin, Marc R Fabian, Nahum Sonenberg, Michal Dadlez, Anna Niedzwiecka
The human GW182 protein plays an essential role in micro(mi)RNA-dependent gene silencing. miRNA silencing is mediated, in part, by a GW182 C-terminal region called the silencing domain, which interacts with the poly(A) binding protein and the CCR4-NOT deadenylase complex to repress protein synthesis. Structural studies of this GW182 fragment are challenging due to its predicted intrinsically disordered character, except for its RRM domain. However, detailed insights into the properties of proteins containing disordered regions can be provided by hydrogen-deuterium exchange mass spectrometry (HDX/MS)...
October 27, 2017: Journal of the American Society for Mass Spectrometry
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