NONE-No attached Diamond beamline
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Open Access
Abstract: Inhibiting the main protease of SARS-CoV-2 is of great interest in tackling the COVID-19 pandemic caused by the virus. Most efforts have been centred on inhibiting the binding site of the enzyme. However, considering allosteric sites, distant from the active or orthosteric site, broadens the search space for drug candidates and confers the advantages of allosteric drug targeting. Here, we report the allosteric communication pathways in the main protease dimer by using two novel fully atomistic graph-theoretical methods: Bond-to-bond propensity, which has been previously successful in identifying allosteric sites in extensive benchmark data sets without a priori knowledge, and Markov transient analysis, which has previously aided in finding novel drug targets in catalytic protein families. Using statistical bootstrapping, we score the highest ranking sites against random sites at similar distances, and we identify four statistically significant putative allosteric sites as good candidates for alternative drug targeting.
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Jul 2022
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NONE-No attached Diamond beamline
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Charles J.
Buchanan
,
Ben
Gaunt
,
Peter J.
Harrison
,
Yun
Yang
,
Jiwei
Liu
,
Aziz
Khan
,
Andrew M.
Giltrap
,
Audrey
Le Bas
,
Philip N.
Ward
,
Kapil
Gupta
,
Maud
Dumoux
,
Tiong Kit
Tan
,
Lisa
Schimaski
,
Sergio
Daga
,
Nicola
Picchiotti
,
Margherita
Baldassarri
,
Elisa
Benetti
,
Chiara
Fallerini
,
Francesca
Fava
,
Annarita
Giliberti
,
Panagiotis I.
Koukos
,
Matthew J.
Davy
,
Abirami
Lakshminarayanan
,
Xiaochao
Xue
,
Georgios
Papadakis
,
Lachlan P.
Deimel
,
Virgínia
Casablancas-Antràs
,
Timothy D. W.
Claridge
,
Alexandre M. J. J.
Bonvin
,
Quentin J.
Sattentau
,
Simone
Furini
,
Marco
Gori
,
Jiandong
Huo
,
Raymond J.
Owens
,
Christiane
Schaffitzel
,
Imre
Berger
,
Alessandra
Renieri
,
James H.
Naismith
,
Andrew J.
Baldwin
,
Benjamin G.
Davis
Open Access
Abstract: Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily-modified pathogen proteins can be confounded by overlapping sugar signals and/or compound with known experimental constraints. ‘Universal saturation transfer analysis’ (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin lineage SARS-CoV-2 spike trimer binds sialoside sugars in an ‘end-on’ manner. uSTA-guided modelling and a high-resolution cryo-electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar-binding in SARS CoV 2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins in deeper human lung as potentially relevant to virulence and/or zoonosis.
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Jun 2022
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NONE-No attached Diamond beamline
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Open Access
Abstract: Two environmentally friendly organics (ethylenediaminetetraacetic acid, EDTA and its easier biodegradabe isomer, ethylenediamine-N, N′-disuccinic acid, EDDS) were used to dope calcium carbonate (CC) nanoparticles intending to increase their adsorptive properties and evaluate adsorption performance (uptake capacity and removal efficiency) for the persistent Reactive Yellow 84 azo dye. Easily synthesized nanomaterials were fully characterized (morphology and size, mineralogy, organic content, surface area, pore size and hydrodynamic diameter). RY84 removal was performed using two consecutive processes: photodegradation after adsorption. The CC-EDTA particles were most efficient for dye removal as compared to the plain and CC-EDDS particles. Adsorption kinetics and isotherms were considered for the CC-EDTA system. 99% removal occurred via adsorption on 1 g/L of adsorbent at 5 mg/L dye concentration and pH of 8 and it decreased to 48% at 60 mg/L. Maximum uptake capacity as described by Langmuir is 39.53 mg/g. As post-adsorption, under UVA irradiation, in the presence of 40 mmol/L H2O2, at dye concentration of 10 mg/L the highest degradation was 49.11%. Substantial decrease of adsorption (ca. 4 times) and photodegradation (ca. 5 times) efficiencies were observed in wastewater effluent as compared to distilled water. The results have important implications to wastewater treatments and appropriate decisions making for the choice of treatment process, process optimization and scaling up to pilot and industrial levels.
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Feb 2022
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NONE-No attached Diamond beamline
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Abstract: In this work, we present a study about the chemical and magnetic properties of thin magnetite/cobalt ferrite bilayers deposited on MgO(001). Two series of samples with different CoxFe3–xO4 stoichiometries (x = 1 and x = 0.5) in combination with Fe3O4 layers of varying thickness were prepared by reactive molecular beam epitaxy. The quality of the respective films were controlled by means of in situ X-ray photelectron spectroscopy and low energy electron diffraction. Stoichiometry and electronic structure were carried out by hard X-ray photoelectron spectroscopy. To determine the cationic distribution and magnetic moments, X-ray magnetic circular dichroism measurements were performed and charge transfer multiplet and sum rule calculations were applied. Here we find an enhanced interface magnetization for the bilayers. Additionally, superconducting quantum interference device measurements showed characteristic exchange-spring behavior.
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Oct 2021
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NONE-No attached Diamond beamline
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H. T. Henry
Chan
,
Marc A.
Moesser
,
Rebecca K.
Walters
,
Tika R.
Malla
,
Rebecca M.
Twidale
,
Tobias
John
,
Helen M.
Deeks
,
Tristan
Johnston-Wood
,
Victor
Mikhailov
,
Richard B.
Sessions
,
William
Dawson
,
Eidarus
Salah
,
Petra
Lukacik
,
Claire
Strain-Damerell
,
C. David
Owen
,
Takahito
Nakajima
,
Katarzyna
Świderek
,
Alessio
Lodola
,
Vicent
Moliner
,
David R.
Glowacki
,
James
Spencer
,
Martin A.
Walsh
,
Christopher J.
Schofield
,
Luigi
Genovese
,
Deborah K.
Shoemark
,
Adrian J.
Mulholland
,
Fernanda
Duarte
,
Garrett M.
Morris
Open Access
Abstract: The main protease (Mpro) of SARS-CoV-2 is central to viral maturation and is a promising drug target, but little is known about structural aspects of how it binds to its 11 natural cleavage sites. We used biophysical and crystallographic data and an array of biomolecular simulation techniques, including automated docking, molecular dynamics (MD) and interactive MD in virtual reality, QM/MM, and linear-scaling DFT, to investigate the molecular features underlying recognition of the natural Mpro substrates. We extensively analysed the subsite interactions of modelled 11-residue cleavage site peptides, crystallographic ligands, and docked COVID Moonshot-designed covalent inhibitors. Our modelling studies reveal remarkable consistency in the hydrogen bonding patterns of the natural Mpro substrates, particularly on the N-terminal side of the scissile bond. They highlight the critical role of interactions beyond the immediate active site in recognition and catalysis, in particular plasticity at the S2 site. Building on our initial Mpro-substrate models, we used predictive saturation variation scanning (PreSaVS) to design peptides with improved affinity. Non-denaturing mass spectrometry and other biophysical analyses confirm these new and effective ‘peptibitors’ inhibit Mpro competitively. Our combined results provide new insights and highlight opportunities for the development of Mpro inhibitors as anti-COVID-19 drugs.
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Oct 2021
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NONE-No attached Diamond beamline
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Open Access
Abstract: The creation and annihilation of magnetic skyrmions are mediated by three-dimensional topological defects known as Bloch points. Investigation of such dynamical processes is important both for understanding the emergence of exotic topological spin textures, and for future engineering of skyrmions in technological applications. However, while the annihilation of skyrmions has been extensively investigated in two dimensions, in three dimensions the phase transitions are considerably more complex. We report field-dependent experimental measurements of metastable skyrmion lifetimes in an archetypal chiral magnet, revealing two distinct regimes. Comparison to supporting three-dimensional geodesic nudged elastic band simulations indicates that these correspond to skyrmion annihilation into either the helical and conical states, each exhibiting a different transition mechanism. The results highlight that the lowest energy magnetic configuration of the system plays a crucial role when considering the emergence and stability of topological spin structures via defect-mediated dynamics.
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Aug 2021
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NONE-No attached Diamond beamline
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Abstract: The occurrence, chemical composition and structural characterization of the new mineral
3+ kernowite, ideally Cu2Fe(AsO4)(OH)4·4H2O, the Fe3+ -analogue of lirconite Cu2Al(AsO4)(OH)4·4H2O, are described. Kernowite occurs on specimens likely sourced from the Wheal Gorland mine, St Day, Cornwall, U.K in the cavities of a quartz-gossan rich in undifferentiated micro-crystalline grey sulphides and poorly crystalline arsenic phases including both pharmacosiderite and olivenite group minerals. The average composition of kernowite determined from several holotype fragments by electron microprobe analysis is Cu1.88(Fe0.79Al0.09)Σ0.88(As1.12O4)(OH)4·3.65H2O. The structure of kernowite has been determined in monoclinic space group I2/a (a non-standard setting of C2/c) by single-crystal X-ray diffraction to R1 = 0.025, wR2 = 0.051, Goodness-of-fit = 1.112. Unit-cell parameters from SCXRD are a = 12.9243(4)Å, b = 7.5401(3)Å, c = 10.0271(3)Å, Beta = 91.267(3), V = 976.91(6)Å3 (Z = 4). The chemical formula of this crystal indicated by SCXRD from refined site-scattering is Cu2(Fe3+0.84(1)Al0.16)AsO4(OH)4·4H2O. The network of hydrogen-bonding has been determined and is similar to that reported for liroconite from Wheal Gorland by Plumhoff et al. (2020).
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May 2021
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NONE-No attached Diamond beamline
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Alice
Douangamath
,
Alisa
Powell
,
Daren
Fearon
,
Patrick M.
Collins
,
Romain
Talon
,
Tobias
Krojer
,
Rachael
Skyner
,
Jose
Brandao-Neto
,
Louise
Dunnett
,
Alexandre
Dias
,
Anthony
Aimon
,
Nicholas M.
Pearce
,
Conor
Wild
,
Tyler J.
Gorrie-Stone
,
Frank
Von Delft
Open Access
Abstract: In fragment-based drug discovery, hundreds or often thousands of compounds smaller than ~300 Da are tested against the protein of interest to identify chemical entities that can be developed into potent drug candidates. Since the compounds are small, interactions are weak, and the screening method must therefore be highly sensitive; moreover, structural information tends to be crucial for elaborating these hits into lead-like compounds. Therefore, protein crystallography has always been a gold-standard technique, yet historically too challenging to find widespread use as a primary screen.
Initial XChem experiments were demonstrated in 2014 and then trialed with academic and industrial collaborators to validate the process. Since then, a large research effort and significant beamtime have streamlined sample preparation, developed a fragment library with rapid follow-up possibilities, automated and improved the capability of I04-1 beamline for unattended data collection, and implemented new tools for data management, analysis and hit identification.
XChem is now a facility for large-scale crystallographic fragment screening, supporting the entire crystals-to-deposition process, and accessible to academic and industrial users worldwide. The peer-reviewed academic user program has been actively developed since 2016, to accommodate projects from as broad a scientific scope as possible, including well-validated as well as exploratory projects. Academic access is allocated through biannual calls for peer-reviewed proposals, and proprietary work is arranged by Diamond's Industrial Liaison group. This workflow has already been routinely applied to over a hundred targets from diverse therapeutic areas, and effectively identifies weak binders (1%-30% hit rate), which both serve as high-quality starting points for compound design and provide extensive structural information on binding sites. The resilience of the process was demonstrated by continued screening of SARS-CoV-2 targets during the COVID-19 pandemic, including a 3-week turn-around for the main protease.
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May 2021
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NONE-No attached Diamond beamline
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Open Access
Abstract: Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult mammalian biology. This Perspective will provide a summary of current and emerging therapeutic opportunities in modulating Wnt signaling, especially through inhibition of Notum carboxylesterase activity. Notum was recently shown to act as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group. Inhibition of Notum activity may represent a new approach to treat disease where aberrant Notum activity has been identified as the underlying cause. Reliable screening technologies are available to identify inhibitors of Notum, and structural studies are accelerating the discovery of new inhibitors. A selection of these hits have been optimized to give fit-for-purpose small molecule inhibitors of Notum. Three noteworthy examples are LP-922056 (26), ABC99 (27), and ARUK3001185 (28), which are complementary chemical tools for exploring the role of Notum in Wnt signaling.
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Mar 2021
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NONE-No attached Diamond beamline
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Kenji
Nawa
,
Demie
Kepaptsoglou
,
Arsham
Ghasemi
,
Philip
Hasnip
,
Guillermo
Bárcena-González
,
Giuseppe
Nicotra
,
Pedro L.
Galindo
,
Quentin M.
Ramasse
,
Kohji
Nakamura
,
Susannah C.
Speller
,
Balati
Kuerbanjiang
,
Thorsten
Hesjedal
,
Vlado K.
Lazarov
Abstract: We present a structural and density-functional theory study of the interface of the quasi-twin-free grown three-dimensional topological insulator
Bi
2
Te
3
on Ge(111). Aberration-corrected scanning transmission electron microscopy and electron energy-loss spectroscopy in combination with first-principles calculations show that the weak van der Waals adhesion between the
Bi
2
Te
3
quintuple layer and Ge can be overcome by forming an additional Te layer at their interface. The first-principles calculations of the formation energy of the additional Te layer show it to be energetically favorable as a result of the strong hybridization between the Te and Ge.
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Feb 2021
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