Krios I-Titan Krios I at Diamond
Krios II-Titan Krios II at Diamond
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Open Access
Abstract: The ATPase Prp16 governs equilibrium between the branching (B∗/C) and exon ligation (C∗/P) conformations of the spliceosome. Here, we present the electron cryomicroscopy reconstruction of the Saccharomyces cerevisiae C-complex spliceosome at 2.8 Å resolution and identify a novel C-complex intermediate (Ci) that elucidates the molecular basis for this equilibrium. The exon-ligation factors Prp18 and Slu7 bind to Ci before ATP hydrolysis by Prp16 can destabilize the branching conformation. Biochemical assays suggest that these pre-bound factors prime the C complex for conversion to C∗ by Prp16. A complete model of the Prp19 complex (NTC) reveals how the branching factors Yju2 and Isy1 are recruited by the NTC before branching. Prp16 remodels Yju2 binding after branching, allowing Yju2 to remain tethered to the NTC in the C∗ complex to promote exon ligation. Our results explain how Prp16 action modulates the dynamic binding of step-specific factors to alternatively stabilize the C or C∗ conformation and establish equilibrium of the catalytic spliceosome.
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Mar 2021
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I11-High Resolution Powder Diffraction
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Alexandra
Morscher
,
Matthew S.
Dyer
,
Benjamin B.
Duff
,
Guopeng
Han
,
Jacinthe
Gamon
,
Luke
Daniels
,
Yun
Dang
,
T. Wesley
Surta
,
Craig M.
Robertson
,
Frédéric
Blanc
,
John B.
Claridge
,
Matthew J.
Rosseinsky
Diamond Proposal Number(s):
[23666]
Open Access
Abstract: A hexagonal analogue, Li6SiO4Cl2, of the cubic lithium argyrodite family of solid electrolytes is isolated by a computation–experiment approach. We show that the argyrodite structure is equivalent to the cubic antiperovskite solid electrolyte structure through anion site and vacancy ordering within a cubic stacking of two close-packed layers. Construction of models that assemble these layers with the combination of hexagonal and cubic stacking motifs, both well known in the large family of perovskite structural variants, followed by energy minimization identifies Li6SiO4Cl2 as a stable candidate composition. Synthesis and structure determination demonstrate that the material adopts the predicted lithium site-ordered structure with a low lithium conductivity of ∼10–10 S cm–1 at room temperature and the predicted hexagonal argyrodite structure above an order–disorder transition at 469.3(1) K. This transition establishes dynamic Li site disorder analogous to that of cubic argyrodite solid electrolytes in hexagonal argyrodite Li6SiO4Cl2 and increases Li-ion mobility observed via NMR and AC impedance spectroscopy. The compositional flexibility of both argyrodite and perovskite alongside this newly established structural connection, which enables the use of hexagonal and cubic stacking motifs, identifies a wealth of unexplored chemistry significant to the field of solid electrolytes.
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Mar 2021
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Derun
Li
,
Yongqi
Deng
,
Abdelghani
Achab
,
Indu
Bharathan
,
Brett Andrew
Hopkins
,
Wensheng
Yu
,
Hongjun
Zhang
,
Sulagna
Sanyal
,
Qinglin
Pu
,
Hua
Zhou
,
Kun
Liu
,
Jongwon
Lim
,
Xavier
Fradera
,
Charles A.
Lesburg
,
Alfred
Lammens
,
Theodore A.
Martinot
,
Ryan D.
Cohen
,
Amy C.
Doty
,
Heidi
Ferguson
,
Elliott B.
Nickbarg
,
Mangeng
Cheng
,
Peter
Spacciapoli
,
Prasanthi
Geda
,
Xuelei
Song
,
Nadya
Smotrov
,
Pravien
Abeywickrema
,
Christine
Andrews
,
Chad
Chamberlin
,
Omar
Mabrouk
,
Patrick
Curran
,
Matthew
Richards
,
Peter
Saradjian
,
J. Richard
Miller
,
Ian
Knemeyer
,
Karin M.
Otte
,
Stella
Vincent
,
Nunzio
Sciammetta
,
Alexander
Pasternak
,
David Jonathan
Bennett
,
Yongxin
Han
Abstract: Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.
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Mar 2021
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I18-Microfocus Spectroscopy
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Diamond Proposal Number(s):
[17304]
Open Access
Abstract: Laser processing is a highly versatile technique for the post-synthesis treatment and modification of transition metal dichalcogenides (TMDCs). However, to date, TMDCs synthesis typically relies on large area CVD growth and lithographic post-processing for nanodevice fabrication, thus relying heavily on complex, capital intensive, vacuum-based processing environments and fabrication tools. This inflexibility necessarily restricts the development of facile, fast, very low-cost synthesis protocols. Here we show that direct, spatially selective synthesis of 2D-TMDCs devices that exhibit excellent electrical, Raman and photoluminescence properties can be realized using laser printing under ambient conditions with minimal lithographic or thermal overheads. Our simple, elegant process can be scaled via conventional laser printing approaches including spatial light modulation and digital light engines to enable mass production protocols such as roll-to-roll processing.
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Mar 2021
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Open Access
Abstract: In situ synchrotron X-ray tomography has been used to observe the initiation and propagation of pits during atmospheric corrosion of aluminium alloy AA2024 under droplets of NaCl and simulated seawater at 21 ± 2 °C and a relative humidity of 85% over a period of 120 minutes. Each complete tomogram took 300 s to collect (pixel size 0.74 µm). Two metastable pits initiated at intermetallic particles, forming a crevice around the edge of the particles. Three other metastable pits formed at sites with no obvious micron-sized features. Only one pit, which had initiated under a fragment of debris, continued to stable growth. Metastable pits initiated sequentially, and all initiation events were accompanied by the formation of one or more bubbles, presumed to be hydrogen. Pit propagation was spatially non-uniform, with rapid growth in local regions while the remainder of the pit remained passive. The growth rate was highest parallel to the rolling direction of the plate. The highest local current density was estimated from the loss of metal between successive measurements to be ~0.5 A/cm2. This is the first time that the transition from initiation to propagation of individual localised pits in an aluminium alloy has been characterised in situ.
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Mar 2021
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[22240]
Open Access
Abstract: A [Mn18] wheel of wheels is obtained from the reaction of MnBr2·4H2O and LH3 in MeOH. The metallic skeleton reveals two asymmetric [MnIII6MnII2] square wheels connected into a larger wheel via two MnII ions. Magnetic susceptibility and magnetisation data reveal competing exchange interactions, supported by computational studies.
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Mar 2021
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[23480]
Open Access
Abstract: Gold(I) bridged dimeric and trimeric structures of a ground state spin S = 1/2 heterometallic {Cr7Ni} wheel have been prepared and studied by continuous wave (CW) and pulsed wave EPR spectrometry. The {Cr7Ni} relaxation time constants (T1 and Tm) show rates matching well with previous observations. Four pulse Double Electron Resonance (DEER) studies suggest presence of more than one conformations. Small Angle X-ray Scattering (SAXS) in conjunction with Molecular Dynamic (MD) Simulations were performed to look at the possible conformations in solution. In line with DEER results, simulation data further indicated more flexible molecular geometry in solution than the one in solid state.
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Mar 2021
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I07-Surface & interface diffraction
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Diamond Proposal Number(s):
[21899]
Abstract: Organic charge transfer complexes (CTCs) with near-infrared absorption received growing interest in the past years, but the details of their photophysics, especially in thin films, remain largely unknown. We combined experimental and computational methods to thoroughly investigate and compare CTCs formed by tetracene with 2,2′-(perfluoronaphthalene-2,6-diylidene)dimalononitrile and 2,3,5,6-tetrafluoro-7,7,8,8,-tetracyanoquinodimethane, respectively. Using ultrafast transient absorption spectroscopy, the photophysics of these small bandgap CTCs was revealed, which is dominated by a sub-picosecond relaxation of the excitons back to the ground state. In equimolar blends, tetracene singlet fission is suppressed while in blends with excess of tetracene reduced lifetimes of tetracene, singlet and triplet excitons were found.
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Mar 2021
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Open Access
Abstract: Batteries are the most abundant form of electrochemical energy storage. Lithium and sodium ion batteries account for a significant portion of the battery market, but high-performance electrochemically active materials still need to be discovered and optimized for these technologies. Recently, tin(II) oxide (SnO) has emerged as a highly promising battery electrode. In this work, we present a facile synthesis method to produce SnO microparticles whose size and shape can be tailored by changing the solvent nature. We study the complex relationship between wet-chemistry synthesis conditions and resulting layered nanoparticle morphology. Furthermore, high-level electronic structure theory, including dispersion corrections to account for van der Waals forces, is employed to enhance our understanding of the underlying chemical mechanisms. The electronic vacuum alignment and surface energies are determined, allowing the prediction of the thermodynamically favoured crystal shape (Wulff construction) and surface-weighted work function. Finally, the synthesized nanomaterials were tested as Li-ion battery anodes, demonstrating significantly enhanced electrochemical performance for morphologies obtained from specific synthesis conditions.
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Mar 2021
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I04-Macromolecular Crystallography
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Open Access
Abstract: The in vitro oxidative folding of proteins has been studied for over sixty years, providing critical insight into protein folding mechanisms. Hirudin, the most potent natural inhibitor of thrombin, is a 65-residue protein with three disulfide bonds, and is viewed as a folding model for a wide range of disulfide-rich proteins. Hirudin’s folding pathway is notorious for its highly heterogeneous intermediates and scrambled isomers, limiting its folding rate and yield in vitro. Aiming to overcome these limitations, we undertake systematic investigation of diselenide bridges at native and non-native positions and investigate their effect on hirudin’s folding, structure and activity. Our studies demonstrate that, regardless of the specific positions of these substitutions, the diselenide crosslinks enhanced the folding rate and yield of the corresponding hirudin analogues, while reducing the complexity and heterogeneity of the process. Moreover, crystal structure analysis confirms that the diselenide substitutions maintained the overall three-dimensional structure of the protein and left its function virtually unchanged. The choice of hirudin as a study model has implications beyond its specific folding mechanism, demonstrating the high potential of diselenide substitutions in the design, preparation and characterization of disulfide-rich proteins.
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Mar 2021
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