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10,283 items found (0 items not approved), displaying 61 to 70.[First/Prev] 3, 4, 5, 6, 7, 8, 9, 10 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-1-Macromolecular Crystallography (fixed wavelength)	Kinetic and structural studies of Trypanosoma and Leishmania phosphofructokinases show evolutionary divergence and identify AMP as a switch regulating glycolysis versus gluconeogenesis Peter M. Fernandes , James Kinkead , Iain W. Mcnae , Monserrat Vasquez-valdivieso , Martin A. Wear , Paul A. M. Michels , Malcolm D. Walkinshaw The Febs Journal 160 DOI: 10.1111/febs.15177 Diamond Proposal Number(s): [1225] Open Access Show Abstract ▼ Abstract: Trypanosomatids possess glycosome organelles that contain much of the glycolytic machinery, including phosphofructokinase (PFK). We present kinetic and structural data for PFK from three human pathogenic trypanosomatids, illustrating intriguing differences that may reflect evolutionary adaptations to differing ecological niches. The activity of Leishmania PFK – to a much larger extent than Trypanosoma PFK – is reliant on AMP for activity regulation, with 1 mm AMP increasing the L. infantum PFK (LiPFK) kcat/K0.5F6P value by 10‐fold, compared to only a 1.3‐ and 1.4‐fold increase for T. cruzi and T. brucei PFK, respectively. We also show that Leishmania PFK melts at a significantly lower (> 15 °C) temperature than Trypanosoma PFKs and that addition of either AMP or ATP results in a marked stabilization of the protein. Sequence comparisons of Trypanosoma spp. and Leishmania spp. show that divergence of the two genera involved amino acid substitutions that occur in the enzyme’s ‘reaching arms’ and ‘embracing arms’ that determine tetramer stability. The dramatic effects of AMP on Leishmania activity compared with the Trypanosoma PFKs may be explained by differences between the T‐to‐R equilibria for the two families, with the low‐melting Leishmania PFK favouring the flexible inactive T‐state in the absence of AMP. Sequence comparisons along with the enzymatic and structural data presented here also suggest there was a loss of AMP‐dependent regulation in Trypanosoma species rather than gain of this characteristic in Leishmania species and that AMP acts as a key regulator in Leishmania governing the balance between glycolysis and gluconeogenesis.	Jan 2020
I04-1-Macromolecular Crystallography (fixed wavelength)	Cocktailed fragment screening by X-ray crystallography of the antibacterial target undecaprenyl pyrophosphate synthase from Acinetobacter baumannii James H. Thorpe , Ian D. Wall , Robert H. Sinnamon , Amy N. Taylor , Robert A. Stavenger Acta Crystallographica Section F Structural Biology Communications 76, 40 - 46 DOI: 10.1107/S2053230X19017199 Diamond Proposal Number(s): [5799] Show Abstract ▼ Abstract: Direct soaking of protein crystals with small-molecule fragments grouped into complementary clusters is a useful technique when assessing the potential of a new crystal system to support structure-guided drug discovery. It provides a robustness check prior to any extensive crystal screening, a double check for assay binding cutoffs and structural data for binding pockets that may or may not be picked out in assay measurements. The structural output from this technique for three novel fragment molecules identified to bind to the antibacterial target Acinetobacter baumannii undecaprenyl pyrophosphate synthase are reported, and the different physicochemical requirements of a successful antibiotic are compared with traditional medicines.	Jan 2020
	Chemo- and regioselective synthesis of acyl-cyclohexenes by a tandem acceptorless dehydrogenation-[1,5]-hydride shift cascade Lewis B. Smith , Roly J. Armstrong , Daniel Matheau-raven , Timothy J. Donohoe Journal Of The American Chemical Society DOI: 10.1021/jacs.9b12296 Open Access Show Abstract ▼ Abstract: An atom-economical methodology to access substituted acyl-cyclohexenes from pentamethylacetophenone and 1,5-diols is described. This process is catalyzed by an iridium(I) catalyst in conjunction with a bulky electron rich phosphine ligand (CataCXium A) which favors acceptorless dehydrogenation over conjugate reduction to the corresponding cyclohexane. The reaction produces water and hydrogen gas as the sole byproducts and a wide range of functionalized acyl-cyclohexene products can be synthesized using this method in very high yields. A series of control experiments were carried out, which revealed that the process is initiated by acceptorless dehydrogenation of the diol followed by a redox-neutral cascade process, which is independent of the iridium catalyst. Deuterium labeling studies established that the key step of this cascade involves a novel base-mediated [1,5]-hydride shift. The cyclohexenyl ketone products could readily be cleaved under mildly acidic conditions to access a range of valuable substituted cyclohexene derivatives.	Jan 2020
Krios I-Titan Krios I at Diamond Krios II-Titan Krios II at Diamond Krios IV-Titan Krios IV at Diamond	A conformational switch in response to Chi converts RecBCD from phage destruction to DNA repair Kaiying Cheng , Martin Wilkinson , Yuriy Chaban , Dale B. Wigley Nature Structural & Molecular Biology 27, 71 - 77 DOI: 10.1038/s41594-019-0355-2 Diamond Proposal Number(s): [19865] Open Access Show Abstract ▼ Abstract: The RecBCD complex plays key roles in phage DNA degradation, CRISPR array acquisition (adaptation) and host DNA repair. The switch between these roles is regulated by a DNA sequence called Chi. We report cryo-EM structures of the Escherichia coli RecBCD complex bound to several different DNA forks containing a Chi sequence, including one in which Chi is recognized and others in which it is not. The Chi-recognized structure shows conformational changes in regions of the protein that contact Chi and reveals a tortuous path taken by the DNA. Sequence specificity arises from interactions with both the RecC subunit and the sequence itself. These structures provide molecular details for how Chi is recognized and insights into the changes that occur in response to Chi binding that switch RecBCD from bacteriophage destruction and CRISPR spacer acquisition to constructive host DNA repair.	Jan 2020
I24-Microfocus Macromolecular Crystallography	Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin Samir Olatunji , Xiaoxiao Yu , Jonathan Bailey , Chia-ying Huang , Marta Zapotoczna , Katherine Bowen , Maja Remškar , Rolf Müller , Eoin M. Scanlan , Joan A. Geoghegan , Vincent Olieric , Martin Caffrey Nature Communications 11 DOI: 10.1038/s41467-019-13724-y Diamond Proposal Number(s): [17810] Open Access Show Abstract ▼ Abstract: Antimicrobial resistance is a major global threat that calls for new antibiotics. Globomycin and myxovirescin are two natural antibiotics that target the lipoprotein-processing enzyme, LspA, thereby compromising the integrity of the bacterial cell envelope. As part of a project aimed at understanding their mechanism of action and for drug development, we provide high-resolution crystal structures of the enzyme from the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) complexed with globomycin and with myxovirescin. Our results reveal an instance of convergent evolution. The two antibiotics possess different molecular structures. Yet, they appear to inhibit identically as non-cleavable tetrahedral intermediate analogs. Remarkably, the two antibiotics superpose along nineteen contiguous atoms that interact similarly with LspA. This 19-atom motif recapitulates a part of the substrate lipoprotein in its proposed binding mode. Incorporating this motif into a scaffold with suitable pharmacokinetic properties should enable the development of effective antibiotics with built-in resistance hardiness.	Jan 2020
I15-1-X-ray Pair Distribution Function (XPDF)	Solvent-free powder synthesis and MOF-CVD thin films of the large-pore metal-organic framework MAF-6 Timothee Stassin , Ivo Stassen , Joao Marreiros , Alexander John Cruz , Rhea Verbeke , Min Tu , Helge Reinsch , Marcel Dickmann , Werner Egger , Ivo F. J. Vankelecom , Dirk E. De Vos , Rob Ameloot Chemistry Of Materials DOI: 10.1021/acs.chemmater.9b03807 Diamond Proposal Number(s): [17279] Show Abstract ▼ Abstract: A simple solvent- and catalyst-free method is presented for the synthesis of the large-pore metal-organic framework (MOF) MAF-6 (RHO-Zn(eIm)2) based on the reaction of ZnO with 2-ethylimidazole vapor at temperatures ≤ 100 °C. By translating this method to a chemical vapor deposition (CVD) protocol, crystalline films of a large-pore material could be deposited for the first time entirely from the vapor phase. A combination of PALS and Kr physisorption measurements confirmed the porosity of these MOF-CVD films and the size of the MAF-6 supercages (diam. ~2 nm), in close agreement with powder data and calculations. MAF-6 powders and films were further characterized by XRD, TGA, SEM, FTIR, PDF and EXAFS. The exceptional uptake capacity of MAF-6 in comparison to ZIF-8 is demonstrated by vapor-phase loading of a molecule larger than the ZIF-8 windows.	Jan 2020
I13-2-Diamond Manchester Imaging	Phase-contrast 3D tomography of HeLa cells grown in PLLA polymer electrospun scaffolds using synchrotron X-rays A. Bhartiya , K. Madi , C. M. Disney , L. Courtois , A. Jupe , F. Zhang , A. J. Bodey , P. Lee , C. Rau , Ian Robinson , M. Yusuf Journal Of Synchrotron Radiation 27, 158 - 163 DOI: 10.1107/S1600577519015583 Diamond Proposal Number(s): [14187] Show Abstract ▼ Abstract: Advanced imaging is useful for understanding the three-dimensional (3D) growth of cells. X-ray tomography serves as a powerful noninvasive, nondestructive technique that can fulfill these purposes by providing information about cell growth within 3D platforms. There are a limited number of studies taking advantage of synchrotron X-rays, which provides a large field of view and suitable resolution to image cells within specific biomaterials. In this study, X-ray synchrotron radiation microtomography at Diamond Light Source and advanced image processing were used to investigate cellular infiltration of HeLa cells within poly L-lactide (PLLA) scaffolds. This study demonstrates that synchrotron X-rays using phase contrast is a useful method to understand the 3D growth of cells in PLLA electrospun scaffolds. Two different fiber diameter (2 and 4 µm) scaffolds with different pore sizes, grown over 2, 5 and 8 days in vitro, were examined for infiltration and cell connectivity. After performing visualization by segmentation of the cells from the fibers, the results clearly show deeper cell growth and higher cellular interconnectivity in the 4 µm fiber diameter scaffold. This indicates the potential for using such 3D technology to study cell–scaffold interactions for future medical use.	Jan 2020
B18-Core EXAFS	Electronic characterization of redox (non)-innocent Fe 2 S 2 reference systems: a multi K-edge X-ray spectroscopic study J. P. H. Oudsen , B. Venderbosch , T. J. Korstanje , M. Tromp Rsc Advances 10, 729 - 738 DOI: 10.1039/C9RA08903A Diamond Proposal Number(s): [13069] Open Access Show Abstract ▼ Abstract: Di-iron dithiolate hydrogenase model complexes are promising systems for electrocatalytic production of dihydrogen and have therefore been spectroscopically and theoretically investigated in this study. The direct effect of ligand substitution on the redox activity of the complex is examined. In order to understand and eventually optimize such systems, we characterised both metal and ligand in detail, using element specific X-ray absorption Fe- and S-K edge XAS. The (electronic) structure of three different [Fe2S2] hydrogenase systems in their non-reduced state was investigated. The effect of one- and two-electron reduction on the (electronic) structure was subsequently investigated. The S K-edge XAS spectra proved to be sensitive to delocalization of the electron density into the aromatic ring. The earlier postulated charge and spin localization in these complexes could now be measured directly using XANES. Moreover, the electron density (from S K-edge XANES) could be directly correlated to the Fe–CO bond length (from Fe K-edge EXAFS), which are in turn both related to the reported catalytic activity of these complexes. The delocalization of the electron density into the conjugated π-system of the aromatic moieties lowers the basicity of the diiron core and since protonation occurs at the diiron (as a rate determining step), lowering the basicity decreases the extent of protonation and consequently the catalytic activity.	Jan 2020
B18-Core EXAFS	Incorporation of Cr III into a Keggin polyoxometalate as a chemical strategy to stabilize a labile {Cr III O 4 } tetrahedral conformation and promote unattended single-ion magnet properties Nadiia I. Gumerova , Alexander Roller , Gerald Giester , Jurek Krzystek , Joan Cano , Annette Rompel Journal Of The American Chemical Society DOI: 10.1021/jacs.9b12797 Diamond Proposal Number(s): [24909] Show Abstract ▼ Abstract: Polyoxometalates (POMs) provide rigid and highly symmetric coordination sites and can be used as a strategy for the stabilization of magnetic ions. Herein, we report a new member of the Keggin archetype – the Cr-centered Keggin anion [α-CrW12O40]5- (CrW12) – with the unusual tetrahedral coordination of CrIII reported for the first time in POMs conferring unattended magnetic properties. POM chemistry has recently presented excellent examples of single molecule and single-ion magnets (SMMs and SIMs) as well as molecular spin qubits; however, the majority of POM-based SIMs reported to date contain lanthanoid ions. CrW12, as the first example of chromium (III) SIM, exhibits slow relaxation of magnetization and quantum tunneling with a single-ion magnetic behavior even above 10 K with an energy barrier for the reversal of the magnetization of 3.0 K. The first 3d-metal SIM based on a non-lacunary Keggin anion is the foundation for a new research area in POM chemistry.	Jan 2020
B21-High Throughput SAXS	Solution structure and oligomeric state of the E. coli glycerol facilitator Mary Hernando , George Orris , Jacqueline Perodeau , Shixing Lei , Fraser G. Ferens , Trushar R. Patel , Jörg Stetefeld , Andrew J. Nieuwkoop , Joe D. O'neil Biochimica Et Biophysica Acta (bba) - Biomembranes DOI: 10.1016/j.bbamem.2020.183191 Diamond Proposal Number(s): [16028] Show Abstract ▼ Abstract: Protein dynamics at atomic resolution can provide deep insights into the biological activities of proteins and enzymes but they can also make structure and dynamics studies challenging. Despite their well-known biological and pharmaceutical importance, integral membrane protein structure and dynamics studies lag behind those of water-soluble proteins mainly owing to solubility problems that result upon their removal from the membrane. Escherichia coli glycerol facilitator (GF) is a member of the aquaglyceroporin family that allows for the highly selective passive diffusion of its substrate glycerol across the inner membrane of the bacterium. Previous molecular dynamics simulations and hydrogen-deuterium exchange studies suggested that protein dynamics play an important role in the passage of glycerol through the protein pore. With the aim of studying GF dynamics by solution and solid-state nuclear magnetic resonance (NMR) spectroscopy we optimized the expression of isotope-labelled GF and explored various solubilizing agents including detergents, osmolytes, amphipols, random heteropolymers, lipid nanodiscs, bicelles and other buffer additives to optimize the solubility and polydispersity of the protein. The GF protein is most stable and soluble in lauryl maltose neopentyl glycol (LMNG), where it exists in a tetramer-octamer equilibrium. The solution structures of the GF tetramer and octamer were determined by negative-stain transmission electron microscopy (TEM), size-exclusion chromatography small-angle X-ray scattering (SEC-SAXS) and solid-state magic-angle spinning NMR spectroscopy. Although NMR sample preparation still needs optimization for full structure and dynamics studies, negative stain TEM and SEC-SAXS revealed low-resolution structures of the detergent-solubilized tetramer and octamer particles. The non-native octamer appears to form from the association of the cytoplasmic faces of two tetramers, the interaction apparently mediated by their disordered N- and C-termini. This information may be useful in future studies directed at reducing the heterogeneity and self-association of the protein.	Jan 2020

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