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12,001 items found (0 items not approved), displaying 51 to 60.[First/Prev] 2, 3, 4, 5, 6, 7, 8, 9 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Crystal structure of ADAMTS13 CUB domains reveals their role in global latency H. J. Kim , Y. Xu , A. Petri , K. Vanhoorelbeke , J. T. B. Crawley , J. Emsley Science Advances 7 DOI: 10.1126/sciadv.abg4403 Diamond Proposal Number(s): [19880] Open Access Show Abstract ▼ Abstract: ADAMTS13 is a plasma metalloprotease that is essential for the regulation of von Willebrand factor (VWF) function, mediator of platelet recruitment to sites of blood vessel damage. ADAMTS13 function is dynamically regulated by structural changes induced by VWF binding that convert it from a latent to active conformation. ADAMTS13 global latency is manifest by the interaction of its C-terminal CUB1-2 domains with its central Spacer domain. We resolved the crystal structure of the ADAMTS13 CUB1-2 domains revealing a previously unreported configuration for the tandem CUB domains. Docking simulations between the CUB1-2 domains with the Spacer domain in combination with enzyme kinetic functional characterization of ADAMTS13 CUB domain mutants enabled the mapping of the CUB1-2 domain site that binds the Spacer domain. Together, these data reveal the molecular basis of the ADAMTS13 Spacer-CUB interaction and the control of ADAMTS13 global latency.	Apr 2021
Theoretical Physics	2p x-ray absorption spectroscopy of 3d transition metal systems Frank M. F. De Groot , Hebatalla Elnaggar , Federica Frati , Ru-Pan Wang , Mario U. Delgado-Jaime , Michel Van Veenendaal , Javier Fernandez-Rodriguez , Maurits W. Haverkort , Robert J. Green , Gerrit Van Der Laan , Yaroslav Kvashnin , Atsushi Hariki , Hidekazu Ikeno , Harry Ramanantoanina , Claude Daul , Bernard Delley , Michael Odelius , Marcus Lundberg , Oliver Kuhn , Sergey I. Bokarev , Eric Shirley , John Vinson , Keith Gilmore , Mauro Stener , Giovanna Fronzoni , Piero Decleva , Peter Kruger , Marius Retegan , Yves Joly , Christian Vorwerk , Claudia Draxl , John Rehr , Arata Tanaka Journal Of Electron Spectroscopy And Related Phenomena 249, 147061 DOI: 10.1016/j.elspec.2021.147061 Open Access Show Abstract ▼ Abstract: This review provides an overview of the different methods and computer codes that are used to interpret 2p x-ray absorption spectra of 3d transition metal ions. We first introduce the basic parameters and give an overview of the methods used. We start with the semi-empirical multiplet codes and compare the different codes that are available. A special chapter is devoted to the user friendly interfaces that have been written on the basis of these codes. Next we discuss the first principle codes based on band structure, including a chapter on Density Functional theory based approaches. We also give an overview of the first-principle multiplet codes that start from a cluster calculation and we discuss the wavefunction based methods, including multi-reference methods. We end the review with a discussion of the link between theory and experiment and discuss the open issues in the spectral analysis.	Apr 2021
	A ride through the epigenetic landscape: aging reversal by reprogramming Lucas Paulo De Lima Camillo , Robert B. A. Quinlan Geroscience 88 DOI: 10.1007/s11357-021-00358-6 Show Abstract ▼ Abstract: Aging has become one of the fastest-growing research topics in biology. However, exactly how the aging process occurs remains unknown. Epigenetics plays a significant role, and several epigenetic interventions can modulate lifespan. This review will explore the interplay between epigenetics and aging, and how epigenetic reprogramming can be harnessed for age reversal. In vivo partial reprogramming holds great promise as a possible therapy, but several limitations remain. Rejuvenation by reprogramming is a young but rapidly expanding subfield in the biology of aging.	Apr 2021
B18-Core EXAFS I20-Scanning-X-ray spectroscopy (XAS/XES)	Structural characterisation studies during synthesis of industrial mixed metal oxide catalysts M. Hammerton Show Abstract ▼ Abstract: Mixed metal oxides are important catalysts in industrial processes that transform bulk hydrocarbons into useful intermediates and products. The oxygen lattice is uniquely able to facilitate redox reactions by rapidly transporting reactive species between active sites. The bulk structure of the lattice governs the availability of electrons, the reactivity of oxygen, and hence the efficiency of catalytic processes. An in-depth understanding of catalyst structure and formation mechanisms is therefore key to the development of effective catalysts. The study of relatively simple oxides gives fundamental knowledge that cannot always be applied to the more complex mixed metal oxide systems that are patented and put into use industrially. The goal of this research is to apply fundamental techniques to complex, commercial catalysts, under industrially relevant conditions, and systematically make sense of the complexity. A range of characterisation techniques that probe different aspects of catalyst structure are used in this thesis during catalyst synthesis to follow (re)organisation pathways of mixed metal oxides and identify the different structures that form. Two mixed metal oxide systems were chosen for investigation: a Cu-spinel based hydrogenation catalyst and a Mo oxide selective oxidation catalyst. The structural transformations during different synthesis steps were analysed using X-ray Absorption Spectroscopy (XAS), X-ray Diffraction (XRD), Infrared (IR), and Raman spectroscopy. New insights into both catalyst systems are discussed and several approaches to catalyst characterisation on different length scales are demonstrated to deliver a holistic understanding of catalyst synthesis.	Apr 2021
I11-High Resolution Powder Diffraction I19-Small Molecule Single Crystal Diffraction	Crystallography companion agent for high-throughput materials discovery Phillip M. Maffettone , Lars Banko , Peng Cui , Yury Lysogorskiy , Marc A. Little , Daniel Olds , Alfred Ludwig , Andrew I. Cooper Nature Computational Science 559 DOI: 10.1038/s43588-021-00059-2 Diamond Proposal Number(s): [15777, 17193] Show Abstract ▼ Abstract: The discovery of new structural and functional materials is driven by phase identification, often using X-ray diffraction (XRD). Automation has accelerated the rate of XRD measurements, greatly outpacing XRD analysis techniques that remain manual, time-consuming, error-prone and impossible to scale. With the advent of autonomous robotic scientists or self-driving laboratories, contemporary techniques prohibit the integration of XRD. Here, we describe a computer program for the autonomous characterization of XRD data, driven by artificial intelligence (AI), for the discovery of new materials. Starting from structural databases, we train an ensemble model using a physically accurate synthetic dataset, which outputs probabilistic classifications—rather than absolutes—to overcome the overconfidence in traditional neural networks. This AI agent behaves as a companion to the researcher, improving accuracy and offering substantial time savings. It is demonstrated on a diverse set of organic and inorganic materials characterization challenges. This method is directly applicable to inverse design approaches and robotic discovery systems, and can be immediately considered for other forms of characterization such as spectroscopy and the pair distribution function.	Apr 2021
	N-Carbamate protected amino acid derived guanidine organocatalysts Zahraa S. Al-Taie , Joseph M. Anderson , Laura Bischoff , Jeppe Christensen , Simon J. Coles , Richard Froom , Mari E. Gibbard , Leigh F. Jones , F. F. J. De Kleijne , Patrick J. Murphy , Emma C. Thompson Tetrahedron 10 DOI: 10.1016/j.tet.2021.132093 Show Abstract ▼ Abstract: We report the preparation of a range of N-protected amino acid derived guanidine organocatalysts and their application to the Michael addition of 2-hydroxy-1,4-napthoquinone to β-nitrostyrene, achieving a maximum ee of 26%. Whilst these catalysts gave poor ees, the structural variation together with the X-ray crystallographic study of the intra- and intermolecular hydrogen bonding reported suggest that the C2-symmetric catalyst are lead compounds for the further development of this methodology.	Apr 2021
	X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease Sebastian Gunther , Patrick Y. A. Reinke , Yaiza Fernández-García , Julia Lieske , Thomas J. Lane , Helen M. Ginn , Faisal H. M. Koua , Christiane Ehrt , Wiebke Ewert , Dominik Oberthuer , Oleksandr Yefanov , Susanne Meier , Kristina Lorenzen , Boris Krichel , Janine-Denise Kopicki , Luca Gelisio , Wolfgang Brehm , Ilona Dunkel , Brandon Seychell , Henry Gieseler , Brenna Norton-Baker , Beatriz Escudero-Pérez , Martin Domaracky , Sofiane Saouane , Alexandra Tolstikova , Thomas A. White , Anna Hänle , Michael Groessler , Holger Fleckenstein , Fabian Trost , Marina Galchenkova , Yaroslav Gevorkov , Chufeng Li , Salah Awel , Ariana Peck , Miriam Barthelmess , Frank Schluenzen , Paulraj Lourdu Xavier , Nadine Werner , Hina Andaleeb , Najeeb Ullah , Sven Falke , Vasundara Srinivasan , Bruno Alves França , Martin Schwinzer , Hévila Brognaro , Cromarte Rogers , Diogo Melo , Joanna J. Zaitseva-Doyle , Juraj Knoska , Gisel E. Peña-Murillo , Aida Rahmani Mashhour , Vincent Hennicke , Pontus Fischer , Johanna Hakanpää , Jan Meyer , Philip Gribbon , Bernhard Ellinger , Maria Kuzikov , Markus Wolf , Andrea R. Beccari , Gleb Bourenkov , David Von Stetten , Guillaume Pompidor , Isabel Bento , Saravanan Panneerselvam , Ivars Karpics , Thomas R. Schneider , Maria Marta Garcia-Alai , Stephan Niebling , Christian Günther , Christina Schmidt , Robin Schubert , Huijong Han , Juliane Boger , Diana C. F. Monteiro , Linlin Zhang , Xinyuanyuan Sun , Jonathan Pletzer-Zelgert , Jan Wollenhaupt , Christian G. Feiler , Manfred S. Weiss , Eike-Christian Schulz , Pedram Mehrabi , Katarina Karničar , Aleksandra Usenik , Jure Loboda , Henning Tidow , Ashwin Chari , Rolf Hilgenfeld , Charlotte Uetrecht , Russell Cox , Andrea Zaliani , Tobias Beck , Matthias Rarey , Stephan Günther , Dusan Turk , Winfried Hinrichs , Henry N. Chapman , Arwen R. Pearson , Christian Betzel , Alke Meents Science DOI: 10.1126/science.abf7945 Open Access Show Abstract ▼ Abstract: The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.	Apr 2021
I04-1-Macromolecular Crystallography (fixed wavelength)	Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking Marion Schuller , Galen J. Correy , Stefan Gahbauer , Daren Fearon , Taiasean Wu , Roberto Efraín Díaz , Iris D. Young , Luan Carvalho Martins , Dominique H. Smith , Ursula Schulze-Gahmen , Tristan W. Owens , Ishan Deshpande , Gregory E. Merz , Aye C. Thwin , Justin T. Biel , Jessica K. Peters , Michelle Moritz , Nadia Herrera , Huong T. Kratochvil , Anthony Aimon , James Bennett , Jose Brandao Neto , Aina E. Cohen , Alexandre Dias , Alice Douangamath , Louise Dunnett , Oleg Fedorov , Matteo P. Ferla , Martin R. Fuchs , Tyler J. Gorrie-Stone , James M. Holton , Michael G. Johnson , Tobias Krojer , George Meigs , Alisa J. Powell , Johannes Gregor Matthias Rack , Victor Rangel , Silvia Russi , Rachael E. Skyner , Clyde A. Smith , Alexei S. Soares , Jennifer L. Wierman , Kang Zhu , Peter O’brien , Natalia Jura , Alan Ashworth , John J. Irwin , Michael C. Thompson , Jason E. Gestwicki , Frank Von Delft , Brian K. Shoichet , James S. Fraser , Ivan Ahel Science Advances 7 DOI: 10.1126/sciadv.abf8711 Diamond Proposal Number(s): [27001] Open Access Show Abstract ▼ Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate–ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.	Apr 2021
	A novel automated screening method for combinatorially generated small molecules Pingshi Yu , Alistair J. Sterling , Jotun Hein Journal Of Chemical Information And Modeling 37 DOI: 10.1021/acs.jcim.0c01462 Show Abstract ▼ Abstract: A main challenge in the enumeration of small-molecule chemical spaces for drug design is to quickly and accurately differentiate between possible and impossible molecules. Current approaches for screening enumerated molecules (e.g., 2D heuristics and 3D force fields) have not been able to achieve a balance between accuracy and speed. We have developed a new automated approach for fast and high-quality screening of small molecules, with the following steps: (1) for each molecule in the set, an ensemble of 2D descriptors as feature encoding is computed; (2) on a random small subset, classification (feasible/infeasible) targets via a 3D-based approach are generated; (3) a classification dataset with the computed features and targets is formed and a machine learning model for predicting the 3D approach’s decisions is trained; and (4) the trained model is used to screen the remainder of the enumerated set. Our approach is ≈8× (7.96× to 8.84×) faster than screening via 3D simulations without significantly sacrificing accuracy; while compared to 2D-based pruning rules, this approach is more accurate, with better coverage of known feasible molecules. Once the topological features and 3D conformer evaluation methods are established, the process can be fully automated, without any additional chemistry expertise.	Apr 2021
I11-High Resolution Powder Diffraction	The origin of catalytic benzylic C‐H oxidation over a redox‐active metal‐organic framework Martin Schroeder , Louis Kimberley , Alena M. Sheveleva , Jiangnan Li , Joseph H. Carter , Xinchen Kang , Gemma L. Smith , Xue Han , Sarah J. Day , Chiu C. Tang , Floriana Tuna , Eric J. L. Mcinnes , Sihai Yang Angewandte Chemie International Edition DOI: 10.1002/anie.202102313 Show Abstract ▼ Abstract: Selective oxidation of benzylic C‐H compounds to ketones is important for the production of a wide range of fine chemicals, and is often achieved using toxic or precious metals catalysts. Here, we report the efficient oxidation of benzylic C‐H groups in a broad range of substrates under mild conditions over a robust metal‐organic framework material, MFM‐170, incorporating redox‐active [Cu2II(O2CR)4] paddlewheel nodes. A comprehensive investigation employing electron paramagnetic resonance (EPR) spectroscopy and synchrotron X‐ray diffraction has identified the critical role of the paddlewheel moiety in activating the oxidant tBuOOH (t‐butyl hydroperoxide) via partial reduction to [CuIICuI(O2CR)4] species.	Apr 2021

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