共查询到20条相似文献,搜索用时 31 毫秒
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Dr. Pierre Thureau Dr. Fabio Ziarelli Dr. André Thévand Prof. Dr. Rachel W. Martin Prof. Dr. Patrick J. Farmer Dr. Stéphane Viel Dr. Giulia Mollica 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(34):10689-10700
Melanin is the most widespread pigment in the animal kingdom. Despite its importance, its detailed structure and overall molecular architecture remain elusive. Both eumelanin (black) and pheomelanin (red) occur in the human body. These two melanin compounds show very different responses to UV‐radiation exposure, which could relate to their microscopic features. Herein, the structural properties and motional behavior of natural eu‐ and pheomelanin extracted from black and red human hair are investigated by means of solid‐state NMR spectroscopy. Several 1D and 2D NMR spectroscopic techniques were combined to highlight the differences between the two forms of the pigment. The quantitative analysis of the 1H NMR wide‐line spectra extracted from 2D 1H–13C LG‐WISE experiments revealed the presence of two dynamically distinguishable components in both forms. Remarkably, the more mobile fraction of the pigment showed a higher mobility with respect to the proteinaceous components that coexist in the melanosome, which is particularly evident for the red pigment. An explanation of the observed effects takes into account the different architecture of the proteinaceous matrix that constitutes the physical substrate onto which melanin polymerizes within the eu‐ and pheomelanosomes. Further insight into the molecular structure of the more mobile fraction of pheomelanin was also obtained by means of the analysis of 2D 1H–13C INEPT experiments. Our view is that not only structural features inherent in the pure pigment, but also the role of the matrix structure in defining the overall melanin supramolecular arrangement and the resulting dynamic behavior of the two melanin compounds should be taken into account to explain their functions. The reported results could pave a new way toward the explanation of the molecular origin of the differences in the photoprotection activity displayed by black and red melanin pigments. 相似文献
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Dr. Filipa Marcelo Catarina Dias Dr. Alice Martins Dr. Paulo J. Madeira Tiago Jorge Prof. M. Helena Florêncio Prof. F. Javier Cañada Prof. Eurico J. Cabrita Prof. Jesús Jiménez‐Barbero Prof. Amélia P. Rauter 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(21):6641-6649
Acetylcholinesterase (AChE) inhibition is one of the most currently available therapies for the management of Alzheimer’s disease (AD) symptoms. In this context, NMR spectroscopy binding studies were accomplished to explain the inhibition of AChE activity by Salvia sclareoides extracts. HPLC‐MS analyses of the acetone, butanol and water extracts eluted with methanol and acidified water showed that rosmarinic acid is present in all the studied samples and is a major constituent of butanol and water extracts. Moreover, luteolin 4′‐O‐glucoside, luteolin 3′,7‐di‐O‐glucoside and luteolin 7‐O‐(6′′‐O‐acetylglucoside) were identified by MS2 and MS3 data acquired during the LC‐MSn runs. Quantification of rosmarinic acid by HPLC with diode‐array detection (DAD) showed that the butanol extract is the richest one in this component (134 μg mg?1 extract). Saturation transfer difference (STD) NMR spectroscopy binding experiments of S. sclareoides crude extracts in the presence of AChE in buffer solution determined rosmarinic acid as the only explicit binder for AChE. Furthermore, the binding epitope and the AChE‐bound conformation of rosmarinic acid were further elucidated by STD and transferred NOE effect (trNOESY) experiments. As a control, NMR spectroscopy binding experiments were also carried out with pure rosmarinic acid, thus confirming the specific interaction and inhibition of this compound against AChE. The binding site of AChE for rosmarinic acid was also investigated by STD‐based competition binding experiments using Donepezil, a drug currently used to treat AD, as a reference. These competition experiments demonstrated that rosmarinic acid does not compete with Donepezil for the same binding site. A 3D model of the molecular complex has been proposed. Therefore, the combination of the NMR spectroscopy based data with molecular modelling has permitted us to detect a new binding site in AChE, which could be used for future drug development. 相似文献
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Prof. Cristina Nativi Dr. Oscar Francesconi Gabriele Gabrielli Irene De Simone Dr. Benedetta Turchetti Dr. Lorenzo Di Cesare Mannelli Prof. Carla Ghelardini Prof. Pietro Buzzini Dr. Stefano Roelens 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(16):5064-5072
The biological activity of a set of structurally related aminopyrrolic synthetic receptors for monosaccharides has been tested versus yeast and yeast‐like microorganisms and compared to their binding affinity toward mannosides. Antibiotic activity comparable to that of well‐known polyene (amphotericin B) or azole (ketoconazole) drugs has been found for some members of the family, along with a general correlation with binding abilities. A systematic structure–activity–affinity investigation shed light on the structural and functional requirements necessary for antibiotic activity and identified the tripodal compound 1 as the most potent compound of the set. Together with toxicity tests and inhibitor localization experiments performed through fluorescence microscopy, these studies led to the characterization of a new class of carbohydrate binding agents possessing antibiotic activity, in which pyrrolic groups precisely structured on a tripodal architecture appear to be responsible for permeability through the cell wall of pathogens, as well as for antibiotic activity inside the cytoplasm. 相似文献
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Site‐Resolved Backbone and Side‐Chain Intermediate Dynamics in a Carbohydrate‐Binding Module Protein Studied by Magic‐Angle Spinning NMR Spectroscopy
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Hadar Ivanir‐Dabora Evgeny Nimerovsky Prof. P. K. Madhu Dr. Amir Goldbourt 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(30):10778-10785
Magic‐angle spinning solid‐state NMR spectroscopy has been applied to study the dynamics of CBM3b–Cbh9A from Clostridium thermocellum (ctCBM3b), a cellulose binding module protein. This 146‐residue protein has a nine‐stranded β‐sandwich fold, in which 35 % of the residues are in the β‐sheet and the remainder are composed of loops and turns. Dynamically averaged 1H‐13C dipolar coupling order parameters were extracted in a site‐specific manner by using a pseudo‐three‐dimensional constant‐time recoupled separated‐local‐field experiment (dipolar‐chemical shift correlation experiment; DIPSHIFT). The backbone‐Cα and Cβ order parameters indicate that the majority of the protein, including turns, is rigid despite having a high content of loops; this suggests that restricted motions of the turns stabilize the loops and create a rigid structure. Water molecules, located in the crystalline interface between protein units, induce an increased dynamics of the interface residues thereby lubricating crystal water‐mediated contacts, whereas other crystal contacts remain rigid. 相似文献
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Dr. Sophie R. Beeren Dr. Sebastian Meier Prof. Ole Hindsgaul 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(48):16314-16320
Branched starch polysaccharides are capable of binding multiple hydrophobic guests, but their exploitation as multivalent hosts and in functional materials is limited by their structural complexity and diversity. Linear α(1–4)‐linked glucose oligosaccharides are known to bind hydrophobic guests inside left‐handed single helices in solution and the solid state. Here, we describe the development of an amphiphilic probe that binds to linear α(1–4)‐linked glucose oligosaccharides and undergoes a conformational switch upon complexation, which gives rise to dramatic changes in the 1H NMR spectrum of the probe. We use this probe to explore hydrophobic binding sites in the branched starch polysaccharides amylopectin and β‐limit dextrin. Diffusion‐ordered (DOSY), nuclear Overhauser effect (NOESY) and chemical shift perturbation (HSQC) NMR experiments are utilised to provide evidence that, in aqueous solution, branched polysaccharides bind hydrophobic guests in well‐defined helical binding sites, similar to those reported for complexation by linear oligosaccharides. By examining the binding affinity of the probe to systematically enzymatically degraded polysaccharides, we deduce that the binding sites for hydrophobic guests can be located on internal as well as external branches and that proximal α(1–6)‐linked branch points weaken but do not prevent complexation. 相似文献
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Dr. Carlos Fernández‐de‐Alba Dr. Hiroki Takahashi Alexandre Richard Yves Chenavier Dr. Lionel Dubois Vincent Maurel Dr. Daniel Lee Dr. Sabine Hediger Dr. Gaël De Paëpe 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(12):4512-4517
Magic‐angle spinning dynamic nuclear polarization (MAS‐DNP) has been proven to be a powerful technique to enhance the sensitivity of solid‐state NMR (SSNMR) in a wide range of systems. Here, we show that DNP can be used to polarize lipids using a lipid‐anchored polarizing agent. More specifically, we introduce a C16‐functionalized biradical, which allows localization of the polarizing agents in the lipid bilayer and DNP experiments to be performed in the absence of excess cryo‐protectant molecules (glycerol, dimethyl sulfoxide, etc.). This constitutes another original example of the matrix‐free DNP approach that we recently introduced. 相似文献
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John V. Hanna Dr. Kevin J. Pike Dr. Thibault Charpentier Dr. Thomas F. Kemp Dr. Mark E. Smith Prof. Bryan E. G. Lucier Robert W. Schurko Prof. Lindsay S. Cahill Dr. 《Chemistry (Weinheim an der Bergstrasse, Germany)》2010,16(10):3222-3239
A variable B0 field static (broadline) NMR study of a large suite of niobate materials has enabled the elucidation of high‐precision measurement of 93Nb NMR interaction parameters such as the isotropic chemical shift (δiso), quadrupole coupling constant and asymmetry parameter (CQ and ηQ), chemical shift span/anisotropy and skew/asymmetry (Ω/Δδ and κ/ηδ) and Euler angles (α, β, γ) describing the relative orientation of the quadrupolar and chemical shift tensorial frames. These measurements have been augmented with ab initio DFT calculations by using WIEN2k and NMR‐CASTEP codes, which corroborate these reported values. Unlike previous assertions made about the inability to detect CSA (chemical shift anisotropy) contributions from NbV in most oxo environments, this study emphasises that a thorough variable B0 approach coupled with the VOCS (variable offset cumulative spectroscopy) technique for the acquisition of undistorted broad (?1/2?+1/2) central transition resonances facilitates the unambiguous observation of both quadrupolar and CSA contributions within these 93Nb broadline data. These measurements reveal that the 93Nb electric field gradient tensor is a particularly sensitive measure of the immediate and extended environments of the NbV positions, with CQ values in the 0 to >80 MHz range being measured; similarly, the δiso (covering an approximately 250 ppm range) and Ω values (covering a 0 to approximately 800 ppm range) characteristic of these niobate systems are also sensitive to structural disposition. However, their systematic rationalisation in terms of the Nb? O bond angles and distances defining the immediate NbV oxo environment is complicated by longer‐range influences that usually involve other heavy elements comprising the structure. It has also been established in this study that the best computational method(s) of analysis for the 93Nb NMR interaction parameters generated here are the all‐electron WIEN2k and the gauge included projector augmented wave (GIPAW) NMR‐CASTEP DFT approaches, which account for the short‐ and long‐range symmetries, periodicities and interaction‐potential characteristics for all elements (and particularly the heavy elements) in comparison with Gaussian 03 methods, which focus on terminated portions of the total structure. 相似文献
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Frontispiece: Matrix‐Free DNP‐Enhanced NMR Spectroscopy of Liposomes Using a Lipid‐Anchored Biradical
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Dr. Carlos Fernández‐de‐Alba Dr. Hiroki Takahashi Alexandre Richard Yves Chenavier Dr. Lionel Dubois Vincent Maurel Dr. Daniel Lee Dr. Sabine Hediger Dr. Gaël De Paëpe 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(12)
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Dr. Sabrina Lusvarghi Dr. Rodolfo Ghirlando Prof. Dr. Chi‐Huey Wong Dr. Carole A. Bewley 《Angewandte Chemie (International ed. in English)》2015,54(19):5603-5608
High‐mannose‐type glycans (HMTGs) decorating viral spike proteins are targets for virus neutralization. For carbohydrate‐binding proteins, multivalency is important for high avidity binding and potent inhibition. To define the chemical determinants controlling multivalent interactions we designed glycopeptide HMTG mimetics with systematically varied mannose valency and spacing. Using the potent antiviral lectin griffithsin (GRFT) as a model, we identified by NMR spectroscopy, SPR, analytical ultracentrifugation, and microcalorimetry glycopeptides that fully recapitulate the specificity and kinetics of binding to Man9GlcNAc2Asn and a synthetic nonamannoside. We find that mannose spacing and valency dictate whether glycopeptides engage GRFT in a face‐to‐face or an intermolecular binding mode. Surprisingly, although face‐to‐face interactions are of higher affinity, intermolecular interactions are longer lived. These findings yield key insights into mechanisms involved in glycan‐mediated viral inhibition. 相似文献
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Jesús Jiménez‐Barbero Prof. Dr. Elisa Dragoni Dr. Chiara Venturi Dr. Federico Nannucci Dr. Ana Ardá Dr. Marco Fontanella Dr. Sabine André Dr. Francisco Javier Cañada Prof. Dr. Hans‐Joachim Gabius Prof. Dr. Cristina Nativi Prof. Dr. 《Chemistry (Weinheim an der Bergstrasse, Germany)》2009,15(40):10423-10431
Efficient cycloaddition of a silylidene‐protected galactal with a suitable heterodiene yielded the basis for a facile diastereoselective route to a glycopeptide‐mimetic scaffold. Its carbohydrate part was further extended by β1–3‐linked galactosylation. The pyranose rings retain their 4C1 chair conformation, as shown by molecular modeling and NMR spectroscopy, and the typical exo‐anomeric geometry was observed for the disaccharide. The expected bioactivity was ascertained by saturation‐transfer‐difference NMR spectroscopy by using the galactoside‐specific plant toxin viscumin as a model lectin. The experimental part was complemented by molecular docking. The described synthetic route and the strategic combination of computational and experimental techniques to reveal conformational properties and bioactivity establish the prepared α‐O‐linked glycopeptide mimetics as promising candidates for further exploitation of this scaffold to give O‐glycans for lectin blocking and vaccination. 相似文献
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Dr. Clelia Cogliati Dr. Laura Ragona Dr. Mariapina D'Onofrio Prof. Ulrich Günther Dr. Sara Whittaker Dr. Christian Ludwig Dr. Simona Tomaselli Dr. Michael Assfalg Prof. Henriette Molinari 《Chemistry (Weinheim an der Bergstrasse, Germany)》2010,16(37):11300-11310
The investigation of multi‐site ligand–protein binding and multi‐step mechanisms is highly demanding. In this work, advanced NMR methodologies such as 2D 1H–15N line‐shape analysis, which allows a reliable investigation of ligand binding occurring on micro‐ to millisecond timescales, have been extended to model a two‐step binding mechanism. The molecular recognition and complex uptake mechanism of two bile salt molecules by lipid carriers is an interesting example that shows that protein dynamics has the potential to modulate the macromolecule–ligand encounter. Kinetic analysis supports a conformational selection model as the initial recognition process in which the dynamics observed in the apo form is essential for ligand uptake, leading to conformations with improved access to the binding cavity. Subsequent multi‐step events could be modelled, for several residues, with a two‐step binding mechanism. The protein in the ligand‐bound state still exhibits a conformational rearrangement that occurs on a very slow timescale, as observed for other proteins of the family. A global mechanism suggesting how bile acids access the macromolecular cavity is thus proposed. 相似文献
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Microsecond Timescale Dynamics of GDP‐Bound Ras Underlies the Formation of Novel Inhibitor‐Binding Pockets
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Dr. Yunyun Mao Haijie Yao Hui Wang Peng Cheng Prof. Dong Long 《Angewandte Chemie (International ed. in English)》2016,55(50):15629-15632
The recent discovery of inhibitory compounds binding to distinct pockets on GDP‐bound Ras has renewed the view on the druggability of this crucial cancer driver. However, the origin of these pockets, which are not readily formed in the crystal structure in the absence of the compounds, is yet unclear. Herein, we explored the intrinsic flexibility of Ras?GDP on microsecond to millisecond timescales using relaxation‐based NMR experiments, and identified substantial slow dynamics with τex of 34 μs at 5 °C, which maps to the regions showing a high level of correlation with those displaying conformational differences between the inhibitor‐bound and free states. These findings, which have been demonstrated in both wild‐type Ras and the oncogenic mutant (G12V), support the mechanism of extended conformational selection for Ras–inhibitor interactions where the small molecules redistribute the protein conformational ensemble favoring the final bound states. 相似文献
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Dr. Simona Tomaselli Dr. Michael Assfalg Dr. Katiuscia Pagano Dr. Clelia Cogliati Dr. Serena Zanzoni Prof. Henriette Molinari Dr. Laura Ragona 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(10):2857-2866
The presence of a disulfide bridge in liver bile acid binding protein (L‐BABP/S‐S) allows for site‐selective binding of two bile acids, glycochenodeoxycholic (GCDA) and glycocholic acid (GCA), differing only in the presence of a hydroxyl group. The protein form devoid of the disulfide bridge (L‐BABP) binds both bile salts without discriminating ability. We investigate the determinants of the molecular recognition process in the formation of the heterotypic L‐BABP/S‐S complex with GCA and GCDA located in the superficial and inner protein sites, respectively. The comparison of the NMR spectroscopy structure of heterotypic holo L‐BABP/S‐S, the first reported for this protein family, with that of the homotypic L‐BABP complex demonstrates that the introduction of a S–S link between adjacent strands changes the conformation of three key residues, which function as hot‐spot mediators of molecular discrimination. The favoured χ1 rotameric states (t, g+ and g? for E99, Q100 and E109 residues, respectively) allow the onset of an extended intramolecular hydrogen‐bond network and the consequent stabilisation of the side‐chain orientation of a buried histidine, which is capable of anchoring a specific ligand. 相似文献
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SBA‐15‐Oxynitrides as a Solid‐Base Catalyst: Effect of Nitridation Temperature on Catalytic Activity
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Baljeet Singh Dr. Kaustubh R. Mote Dr. C. S. Gopinath Prof. Dr. P. K. Madhu Prof. Dr. Vivek Polshettiwar 《Angewandte Chemie (International ed. in English)》2015,54(20):5985-5989
Solid bases, such as SBA‐15‐oxynitrides, have attracted considerable interest for potential applications as catalysts in important industrial processes. Reported herein is that by simply tuning the temperature of nitridation (ammonolysis), the catalytic activity of these solid bases can be enhanced. Solid‐state NMR spectroscopy and XPS studies provided the reasoning behind this change in activity. 相似文献