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Instruments / Technical Area	Publication Details	Published
	Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease Vasundara Srinivasan , Hévila Brognaro , Prince R. Prabhu , Edmarcia Elisa De Souza , Sebastian Günther , Patrick Y. A. Reinke , Thomas J. Lane , Helen Ginn , Huijong Han , Wiebke Ewert , Janina Sprenger , Faisal H. M. Koua , Sven Falke , Nadine Werner , Hina Andaleeb , Najeeb Ullah , Bruno Alves Franca , Mengying Wang , Angélica Luana C. Barra , Markus Perbandt , Martin Schwinzer , Christina Schmidt , Lea Brings , Kristina Lorenzen , Robin Schubert , Rafael Rahal Guaragna Machado , Erika Donizette Candido , Danielle Bruna Leal Oliveira , Edison Luiz Durigon , Stephan Niebling , Angelica Struve Garcia , Oleksandr Yefanov , Julia Lieske , Luca Gelisio , Martin Domaracky , Philipp Middendorf , Michael Groessler , Fabian Trost , Marina Galchenkova , Aida Rahmani Mashhour , Sofiane Saouane , Johanna Hakanpää , Markus Wolf , Maria Garcia Alai , Dusan Turk , Arwen R. Pearson , Henry N. Chapman , Winfried Hinrichs , Carsten Wrenger , Alke Meents , Christian Betzel Communications Biology 5 DOI: 10.1038/s42003-022-03737-7 Open Access Show Abstract ▼ Abstract: SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host’s innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections.	Aug 2022
	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
I03-Macromolecular Crystallography	Megahertz serial crystallography Max O. Wiedorn , Dominik Oberthuer , Richard Bean , Robin Schubert , Nadine Werner , Brian Abbey , Martin Aepfelbacher , Luigi Adriano , Aschkan Allahgholi , Nasser Al-Qudami , Jakob Andreasson , Steve Aplin , Salah Awel , Kartik Ayyer , Saša Bajt , Imrich Barák , Sadia Bari , Johan Bielecki , Sabine Botha , Djelloul Boukhelef , Wolfgang Brehm , Sandor Brockhauser , Igor Cheviakov , Matthew A. Coleman , Francisco Cruz-Mazo , Cyril Danilevski , Connie Darmanin , R. Bruce Doak , Martin Domaracky , Katerina Dörner , Yang Du , Hans Fangohr , Holger Fleckenstein , Matthias Frank , Petra Fromme , Alfonso M. Gañán-Calvo , Yaroslav Gevorkov , Klaus Giewekemeyer , Helen Mary Ginn , Heinz Graafsma , Rita Graceffa , Dominic Greiffenberg , Lars Gumprecht , Peter Göttlicher , Janos Hajdu , Steffen Hauf , Michael Heymann , Susannah Holmes , Daniel A. Horke , Mark S. Hunter , Siegfried Imlau , Alexander Kaukher , Yoonhee Kim , Alexander Klyuev , Juraj Knoška , Bostjan Kobe , Manuela Kuhn , Christopher Kupitz , Jochen Küpper , Janine Mia Lahey-Rudolph , Torsten Laurus , Karoline Le Cong , Romain Letrun , P. Lourdu Xavier , Luis Maia , Filipe R. N. C. Maia , Valerio Mariani , Marc Messerschmidt , Markus Metz , Davide Mezza , Thomas Michelat , Grant Mills , Diana C. F. Monteiro , Andrew Morgan , Kerstin Mühlig , Anna Munke , Astrid Münnich , Julia Nette , Keith A. Nugent , Theresa Nuguid , Allen M. Orville , Suraj Pandey , Gisel Pena , Pablo Villanueva-Perez , Jennifer Poehlsen , Gianpietro Previtali , Lars Redecke , Winnie Maria Riekehr , Holger Rohde , Adam Round , Tatiana Safenreiter , Iosifina Sarrou , Tokushi Sato , Marius Schmidt , Bernd Schmitt , Robert Schönherr , Joachim Schulz , Jonas A. Sellberg , M. Marvin Seibert , Carolin Seuring , Megan L. Shelby , Robert L. Shoeman , Marcin Sikorski , Alessandro Silenzi , Claudiu A. Stan , Xintian Shi , Stephan Stern , Jola Sztuk-Dambietz , Janusz Szuba , Aleksandra Tolstikova , Martin Trebbin , Ulrich Trunk , Patrik Vagovic , Thomas Ve , Britta Weinhausen , Thomas A. White , Krzysztof Wrona , Chen Xu , Oleksandr Yefanov , Nadia Zatsepin , Jiaguo Zhang , Markus Perbandt , Adrian P. Mancuso , Christian Betzel , Henry Chapman , Anton Barty Nature Communications 9 DOI: 10.1038/s41467-018-06156-7 Open Access Show Abstract ▼ Abstract: The new European X-ray Free-Electron Laser is the first X-ray free-electron laser capable of delivering X-ray pulses with a megahertz inter-pulse spacing, more than four orders of magnitude higher than previously possible. However, to date, it has been unclear whether it would indeed be possible to measure high-quality diffraction data at megahertz pulse repetition rates. Here, we show that high-quality structures can indeed be obtained using currently available operating conditions at the European XFEL. We present two complete data sets, one from the well-known model system lysozyme and the other from a so far unknown complex of a β-lactamase from K. pneumoniae involved in antibiotic resistance. This result opens up megahertz serial femtosecond crystallography (SFX) as a tool for reliable structure determination, substrate screening and the efficient measurement of the evolution and dynamics of molecular structures using megahertz repetition rate pulses available at this new class of X-ray laser source.	Oct 2018
I04-Macromolecular Crystallography	Crystal structure of the human tRNAGly microhelix isoacceptor G9990 at 1.18A resolution A. Eichert , M. Perbandt , A. Schreiber , J. P. Fürste , C. Betzel , V. A. Erdmann , C. Förster Biochemical And Biophysical Research Communications 380, 503 - 507 DOI: 10.1016/j.bbrc.2009.01.127 PMID: 19284994 Show Abstract ▼ Abstract: The tRNAGly/Glycyl-tRNA synthetase system belongs to the so called ‘class II’ in which tRNA identity elements consist of relative few and simple motifs, as compared to ‘class I’ where the tRNA determinants are more complicated and spread over different parts of the tRNA, mostly including the anticodon. The determinants from ‘class II’ although, are located in the aminoacyl stem and sometimes include the discriminator base. There exist predominant structure differences for the Glycyl-tRNA-synthetases and for the tRNAGly identity elements comparing eucaryotic/archaebacterial and eubacterial systems. We focus on comparative X-ray structure analysis of tRNAGly acceptor stem microhelices from different organisms. Here, we report the X-ray structure of the human tRNAGly microhelix isoacceptor G9990 at 1.18 Å resolution. Superposition experiments to another human tRNAGly microhelix and a detailed comparison of the RNA hydration patterns show a great number of water molecules with identical positions in both RNAs. This is the first structure comparison of hydration layers from two isoacceptor tRNA microhelices with a naturally occurring base pair exchange.	Mar 2009

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Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease