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34 results on '"Tolstikova, Alexandra"'

1. SARS-CoV-2 Mpro responds to oxidation by forming disulfide and NOS/SONOS bonds

Author

Reinke, Patrick Y. A., Schubert, Robin, Oberthür, Dominik, Galchenkova, Marina, Rahmani Mashhour, Aida, Günther, Sebastian, Chretien, Anaïs, Round, Adam, Seychell, Brandon Charles, Norton-Baker, Brenna, Kim, Chan, Schmidt, Christina, Koua, Faisal H. M., Tolstikova, Alexandra, Ewert, Wiebke, Peña Murillo, Gisel Esperanza, Mills, Grant, Kirkwood, Henry, Brognaro, Hévila, Han, Huijong, Koliyadu, Jayanath, Schulz, Joachim, Bielecki, Johan, Lieske, Julia, Maracke, Julia, Knoska, Juraj, Lorenzen, Kristina, Brings, Lea, Sikorski, Marcin, Kloos, Marco, Vakili, Mohammad, Vagovic, Patrik, Middendorf, Philipp, de Wijn, Raphael, Bean, Richard, Letrun, Romain, Han, Seonghyun, Falke, Sven, Geng, Tian, Sato, Tokushi, Srinivasan, Vasundara, Kim, Yoonhee, Yefanov, Oleksandr M., Gelisio, Luca, Beck, Tobias, Doré, Andrew S., Mancuso, Adrian P., Betzel, Christian, Bajt, Saša, Redecke, Lars, Chapman, Henry N., Meents, Alke, Turk, Dušan, Hinrichs, Winfried, and Lane, Thomas J.

Published
2024
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2. Room-temperature structural studies of SARS-CoV-2 protein NendoU with an X-ray free-electron laser.

Author

Jernigan, Rebecca J, Logeswaran, Dhenugen, Doppler, Diandra, Nagaratnam, Nirupa, Sonker, Mukul, Yang, Jay-How, Ketawala, Gihan, Martin-Garcia, Jose M, Shelby, Megan L, Grant, Thomas D, Mariani, Valerio, Tolstikova, Alexandra, Sheikh, Michelle Z, Yung, Mimi Cho, Coleman, Matthew A, Zaare, Sahba, Kaschner, Emily K, Rabbani, Mohammad Towshif, Nazari, Reza, Zacks, Michele A, Hayes, Brandon, Sierra, Raymond G, Hunter, Mark S, Lisova, Stella, Batyuk, Alexander, Kupitz, Christopher, Boutet, Sebastien, Hansen, Debra T, Kirian, Richard A, Schmidt, Marius, Fromme, Raimund, Frank, Matthias, Ros, Alexandra, Chen, Julian J-L, Botha, Sabine, and Fromme, Petra

Subjects
Humans, Crystallography, X-Ray, Lasers, Temperature, Electrons, COVID-19, SARS-CoV-2, NSP15, NendoU, X-ray free-electron laser, serial femtosecond crystallography, Prevention, Infectious Diseases, Emerging Infectious Diseases, Vaccine Related, Biodefense, Infection, Chemical Sciences, Biological Sciences, Information and Computing Sciences, Biophysics
Abstract

NendoU from SARS-CoV-2 is responsible for the virus's ability to evade the innate immune system by cleaving the polyuridine leader sequence of antisense viral RNA. Here we report the room-temperature structure of NendoU, solved by serial femtosecond crystallography at an X-ray free-electron laser to 2.6 Å resolution. The room-temperature structure provides insight into the flexibility, dynamics, and other intrinsic properties of NendoU, with indications that the enzyme functions as an allosteric switch. Functional studies examining cleavage specificity in solution and in crystals support the uridine-purine cleavage preference, and we demonstrate that enzyme activity is fully maintained in crystal form. Optimizing the purification of NendoU and identifying suitable crystallization conditions set the benchmark for future time-resolved serial femtosecond crystallography studies. This could advance the design of antivirals with higher efficacy in treating coronaviral infections, since drugs that block allosteric conformational changes are less prone to drug resistance.

Published
2023

3. Heterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam

Author

Malla, Tek Narsingh, Zielinski, Kara, Aldama, Luis, Bajt, Sasa, Feliz, Denisse, Hayes, Brendon, Hunter, Mark, Kupitz, Christopher, Lisova, Stella, Knoska, Juraj, Martin-Garcia, Jose Manuel, Mariani, Valerio, Pandey, Suraj, Poudyal, Ishwor, Sierra, Raymond G., Tolstikova, Alexandra, Yefanov, Oleksandr, Yoon, Chung Hong, Ourmazd, Abbas, Fromme, Petra, Schwander, Peter, Barty, Anton, Chapman, Henry N., Stojkovic, Emina A., Batyuk, Alexander, Boutet, Sébastien, Phillips, Jr., George N., Pollack, Lois, and Schmidt, Marius

Published
2023
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4. Observation of substrate diffusion and ligand binding in enzyme crystals using high-repetition-rate mix-and-inject serial crystallography

Author

Pandey, Suraj, Calvey, George, Katz, Andrea M, Malla, Tek Narsingh, Koua, Faisal HM, Martin-Garcia, Jose M, Poudyal, Ishwor, Yang, Jay-How, Vakili, Mohammad, Yefanov, Oleksandr, Zielinski, Kara A, Bajt, Sasa, Awel, Salah, Doerner, Katarina, Frank, Matthias, Gelisio, Luca, Jernigan, Rebecca, Kirkwood, Henry, Kloos, Marco, Koliyadu, Jayanath, Mariani, Valerio, Miller, Mitchell D, Mills, Grant, Nelson, Garrett, Olmos, Jose L, Sadri, Alireza, Sato, Tokushi, Tolstikova, Alexandra, Xu, Weijun, Ourmazd, Abbas, Spence, John CH, Schwander, Peter, Barty, Anton, Chapman, Henry N, Fromme, Petra, Mancuso, Adrian P, Phillips, George N, Bean, Richard, Pollack, Lois, and Schmidt, Marius

Subjects
Tuberculosis, Rare Diseases, Good Health and Well Being, substrate diffusion in crystals, antibiotic resistance, beta-lactamases, enzyme kinetics, irreversible inhibition, mix-and-inject serial crystallography, serial femtosecond crystallography, European X-ray Free-Electron Laser, megahertz pulse-repetition rate, protein structure determination, drug discovery, ceftriaxone, sulbactam, X-ray crystallography, enzyme mechanisms, β-lactamases, Atomic, Molecular, Nuclear, Particle and Plasma Physics, Condensed Matter Physics, Physical Chemistry (incl. Structural)
Abstract

Here, we illustrate what happens inside the catalytic cleft of an enzyme when substrate or ligand binds on single-millisecond timescales. The initial phase of the enzymatic cycle is observed with near-atomic resolution using the most advanced X-ray source currently available: the European XFEL (EuXFEL). The high repetition rate of the EuXFEL combined with our mix-and-inject technology enables the initial phase of ceftriaxone binding to the Mycobacterium tuberculosis β-lactamase to be followed using time-resolved crystallography in real time. It is shown how a diffusion coefficient in enzyme crystals can be derived directly from the X-ray data, enabling the determination of ligand and enzyme-ligand concentrations at any position in the crystal volume as a function of time. In addition, the structure of the irreversible inhibitor sulbactam bound to the enzyme at a 66 ms time delay after mixing is described. This demonstrates that the EuXFEL can be used as an important tool for biomedically relevant research.

Published
2021

5. Time-resolved serial femtosecond crystallography at the European XFEL

Author

Pandey, Suraj, Bean, Richard, Sato, Tokushi, Poudyal, Ishwor, Bielecki, Johan, Cruz Villarreal, Jorvani, Yefanov, Oleksandr, Mariani, Valerio, White, Thomas A, Kupitz, Christopher, Hunter, Mark, Abdellatif, Mohamed H, Bajt, Saša, Bondar, Valerii, Echelmeier, Austin, Doppler, Diandra, Emons, Moritz, Frank, Matthias, Fromme, Raimund, Gevorkov, Yaroslav, Giovanetti, Gabriele, Jiang, Man, Kim, Daihyun, Kim, Yoonhee, Kirkwood, Henry, Klimovskaia, Anna, Knoska, Juraj, Koua, Faisal HM, Letrun, Romain, Lisova, Stella, Maia, Luis, Mazalova, Victoria, Meza, Domingo, Michelat, Thomas, Ourmazd, Abbas, Palmer, Guido, Ramilli, Marco, Schubert, Robin, Schwander, Peter, Silenzi, Alessandro, Sztuk-Dambietz, Jolanta, Tolstikova, Alexandra, Chapman, Henry N, Ros, Alexandra, Barty, Anton, Fromme, Petra, Mancuso, Adrian P, and Schmidt, Marius

Subjects
Biochemistry and Cell Biology, Biological Sciences, Bacterial Proteins, Crystallography, X-Ray, Light, Models, Molecular, Photoreceptors, Microbial, Protein Conformation, Time Factors, Technology, Medical and Health Sciences, Developmental Biology, Biological sciences
Abstract

The European XFEL (EuXFEL) is a 3.4-km long X-ray source, which produces femtosecond, ultrabrilliant and spatially coherent X-ray pulses at megahertz (MHz) repetition rates. This X-ray source has been designed to enable the observation of ultrafast processes with near-atomic spatial resolution. Time-resolved crystallographic investigations on biological macromolecules belong to an important class of experiments that explore fundamental and functional structural displacements in these molecules. Due to the unusual MHz X-ray pulse structure at the EuXFEL, these experiments are challenging. Here, we demonstrate how a biological reaction can be followed on ultrafast timescales at the EuXFEL. We investigate the picosecond time range in the photocycle of photoactive yellow protein (PYP) with MHz X-ray pulse rates. We show that difference electron density maps of excellent quality can be obtained. The results connect the previously explored femtosecond PYP dynamics to timescales accessible at synchrotrons. This opens the door to a wide range of time-resolved studies at the EuXFEL.

Published
2020

6. Cooperative allostery and structural dynamics of streptavidin at cryogenic- and ambient-temperature

Author

Ayan, Esra, Yuksel, Busra, Destan, Ebru, Ertem, Fatma Betul, Yildirim, Gunseli, Eren, Meryem, Yefanov, Oleksandr M., Barty, Anton, Tolstikova, Alexandra, Ketawala, Gihan K., Botha, Sabine, Dao, E. Han, Hayes, Brandon, Liang, Mengning, Seaberg, Matthew H., Hunter, Mark S., Batyuk, Alexander, Mariani, Valerio, Su, Zhen, Poitevin, Frederic, Yoon, Chun Hong, Kupitz, Christopher, Cohen, Aina, Doukov, Tzanko, Sierra, Raymond G., Dağ, Çağdaş, and DeMirci, Hasan

Published
2022
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7. Femtosecond x-ray diffraction from an aerosolized beam of protein nanocrystals

Author

Awel, Salah, Kirian, Richard A., Wiedorn, Max O., Beyerlein, Kenneth R., Roth, Nils, Horke, Daniel A., Oberthür, Dominik, Knoska, Juraj, Mariani, Valerio, Morgan, Andrew, Adriano, Luigi, Tolstikova, Alexandra, Xavier, P. Lourdu, Yefanov, Oleksandr, Aquila, Andrew, Barty, Anton, Roy-Chowdhury, Shatabdi, Hunter, Mark S., James, Daniel, Robinson, Joseph S., Weierstall, Uwe, Rode, Andrei V., Bajt, Saša, Küpper, Jochen, and Chapman, Henry N.

Subjects
Physics - Biological Physics
Abstract

We demonstrate near-atomic-resolution Bragg diffraction from aerosolized single granulovirus crystals using an x-ray free-electron laser. The form of the aerosol injector is nearly identical to conventional liquid-microjet nozzles, but the x-ray-scattering background is reduced by several orders of magnitude by the use of helium carrier gas rather than liquid. This approach provides a route to study the weak diffuse or lattice-transform signal arising from small crystals. The high speed of the particles is particularly well suited to upcoming MHz-repetition-rate x-ray free-electron lasers.

Published
2017
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8. Data reduction in protein serial crystallography

Author

Galchenkova, Marina, primary, Tolstikova, Alexandra, additional, Klopprogge, Bjarne, additional, Sprenger, Janina, additional, Oberthuer, Dominik, additional, Brehm, Wolfgang, additional, White, Thomas A., additional, Barty, Anton, additional, Chapman, Henry N., additional, and Yefanov, Oleksandr, additional

Published
2024
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9. Heterogeneity in the M. tuberculosis β-Lactamase Inhibition by Sulbactam

Author

Schmidt, Marius, primary, Malla, Tek Narsingh, additional, Zielinski, Kara, additional, Aldama, Luis, additional, Bajt, Sasa, additional, Feliz, Denisse, additional, Hayes, Brandon, additional, Hunter, Mark, additional, Kupitz, Christopher, additional, Lisova, Stella, additional, Knoska, Juraj, additional, Martin-Garcia, Jose, additional, Mariani, Valerio, additional, Pandey, Suraj, additional, Poudyal, Ishwor, additional, Sierra, Raymond, additional, Tolstikova, Alexandra, additional, Yefanov, Oleksandr, additional, Yoon, Ching Hong, additional, Ourmazd, Abbas, additional, Fromme, Petra, additional, Schwander, Peter, additional, Barty, Anton, additional, Chapman, Henry, additional, Stojković, Emina, additional, Batyuk, Alexander, additional, Boutet, Sébastien, additional, Phillips, George, additional, and Pollack, Lois, additional

Published
2023
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10. Electrically stimulated droplet injector for reduced sample consumption in serial crystallography

Author

Sonker, Mukul, primary, Doppler, Diandra, additional, Egatz-Gomez, Ana, additional, Zaare, Sahba, additional, Rabbani, Mohammad T., additional, Manna, Abhik, additional, Cruz Villarreal, Jorvani, additional, Nelson, Garrett, additional, Ketawala, Gihan K., additional, Karpos, Konstantinos, additional, Alvarez, Roberto C., additional, Nazari, Reza, additional, Thifault, Darren, additional, Jernigan, Rebecca, additional, Oberthür, Dominik, additional, Han, Huijong, additional, Sierra, Raymond, additional, Hunter, Mark S., additional, Batyuk, Alexander, additional, Kupitz, Christopher J., additional, Sublett, Robert E., additional, Poitevin, Frederic, additional, Lisova, Stella, additional, Mariani, Valerio, additional, Tolstikova, Alexandra, additional, Boutet, Sebastien, additional, Messerschmidt, Marc, additional, Meza-Aguilar, J. Domingo, additional, Fromme, Raimund, additional, Martin-Garcia, Jose M., additional, Botha, Sabine, additional, Fromme, Petra, additional, Grant, Thomas D., additional, Kirian, Richard A., additional, and Ros, Alexandra, additional

Published
2022
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11. Electrically stimulated droplet injector for reduced sample consumption in serial crystallography

Author

National Science Foundation (US), National Institutes of Health (US), Department of Energy (US), Max Planck Institute for Medical Research, Sonker, Mukul, Doppler, Diandra, Egatz-Gomez, Ana, Zaare, Sahba, Rabbani, Mohammad T., Manna, Abhik, Cruz Villarreal, Jorvani, Nelson, Garrett, Ketawala, Gihan K., Karpos, Konstantinos, Alvarez, Roberto C., Nazari, Reza, Thifault, Darren, Jernigan, Rebecca, Oberthür, Dominik, Han, Huijong, Sierra, Raymond, Hunter, Mark S., Batyuk, Alexander, Kupitz, Christopher J., Sublett, Robert E., Poitevin, Frederic, Lisova, Stella, Mariani, Valerio, Tolstikova, Alexandra, Boutet, Sebastien, Messerschmidt, Marc, Meza-Aguilar, J Domingo, Fromme, Raimund, Martín-García, Jose Manuel, Botha, Sabine, Fromme, Petra, Grant, Thomas D., Kirian, Richard A., Ros, Alexandra, National Science Foundation (US), National Institutes of Health (US), Department of Energy (US), Max Planck Institute for Medical Research, Sonker, Mukul, Doppler, Diandra, Egatz-Gomez, Ana, Zaare, Sahba, Rabbani, Mohammad T., Manna, Abhik, Cruz Villarreal, Jorvani, Nelson, Garrett, Ketawala, Gihan K., Karpos, Konstantinos, Alvarez, Roberto C., Nazari, Reza, Thifault, Darren, Jernigan, Rebecca, Oberthür, Dominik, Han, Huijong, Sierra, Raymond, Hunter, Mark S., Batyuk, Alexander, Kupitz, Christopher J., Sublett, Robert E., Poitevin, Frederic, Lisova, Stella, Mariani, Valerio, Tolstikova, Alexandra, Boutet, Sebastien, Messerschmidt, Marc, Meza-Aguilar, J Domingo, Fromme, Raimund, Martín-García, Jose Manuel, Botha, Sabine, Fromme, Petra, Grant, Thomas D., Kirian, Richard A., and Ros, Alexandra

Abstract

With advances in X-ray free-electron lasers (XFELs), serial femtosecond crystallography (SFX) has enabled the static and dynamic structure determination for challenging proteins such as membrane protein complexes. In SFX with XFELs, the crystals are typically destroyed after interacting with a single XFEL pulse. Therefore, thousands of new crystals must be sequentially introduced into the X-ray beam to collect full data sets. Because of the serial nature of any SFX experiment, up to 99% of the sample delivered to the X-ray beam during its "off-time" between X-ray pulses is wasted due to the intrinsic pulsed nature of all current XFELs. To solve this major problem of large and often limiting sample consumption, we report on improvements of a revolutionary sample-saving method that is compatible with all current XFELs. We previously reported 3D-printed injection devices coupled with gas dynamic virtual nozzles (GDVNs) capable of generating samples containing droplets segmented by an immiscible oil phase for jetting crystal-laden droplets into the path of an XFEL. Here, we have further improved the device design by including metal electrodes inducing electrowetting effects for improved control over droplet generation frequency to stimulate the droplet release to matching the XFEL repetition rate by employing an electrical feedback mechanism. We report the improvements in this electrically triggered segmented flow approach for sample conservation in comparison with a continuous GDVN injection using the microcrystals of lysozyme and 3-deoxy-D-manno-octulosonate 8-phosphate synthase and report the segmented flow approach for sample injection applied at the Macromolecular Femtosecond Crystallography instrument at the Linear Coherent Light Source for the first time.

Published
2022

12. Cooperative allostery and structural dynamics of streptavidin at cryogenic- and ambient-temperature

Author

Dağ, Çağdaş; Ayan, Esra; Yüksel, Büşra; Destan, Ebru; Ertem, Fatma Betül; Yıldırım, Günseli; Eren, Meryem; Demirci, Hasan (ORCID 0000-0002-9135-5397 & YÖK ID 307350), Yefanov, Oleksandr M.; Barty, Anton; Tolstikova, Alexandra; Ketawala, Gihan K.; Botha, Sabine; Dao, E. Han; Hayes, Brandon; Liang, Mengning; Seaberg, Matthew H.; Hunter, Mark S.; Batyuk, Alexander; Mariani, Valerio; Su, Zhen; Poitevin, Frederic; Yoon, Chun Hong; Kupitz, Christopher; Cohen, Aina; Doukov, Tzanko; Sierra, Raymond G., Graduate School of Sciences and Engineering; College of Engineering, Department of Molecular Biology and Genetics, Dağ, Çağdaş; Ayan, Esra; Yüksel, Büşra; Destan, Ebru; Ertem, Fatma Betül; Yıldırım, Günseli; Eren, Meryem; Demirci, Hasan (ORCID 0000-0002-9135-5397 & YÖK ID 307350), Yefanov, Oleksandr M.; Barty, Anton; Tolstikova, Alexandra; Ketawala, Gihan K.; Botha, Sabine; Dao, E. Han; Hayes, Brandon; Liang, Mengning; Seaberg, Matthew H.; Hunter, Mark S.; Batyuk, Alexander; Mariani, Valerio; Su, Zhen; Poitevin, Frederic; Yoon, Chun Hong; Kupitz, Christopher; Cohen, Aina; Doukov, Tzanko; Sierra, Raymond G., Graduate School of Sciences and Engineering; College of Engineering, and Department of Molecular Biology and Genetics

Abstract

Ayan et al. report two structures of the protein streptavidin - one at ambient temperature determined using serial femtosecond crystallography and a second one determined at cryogenic temperature. These results provide insights into the structural dynamics of apo streptavidin and reveal a cooperative allostery between monomers for binding to biotin, and the findings are supported by GNM analysis. Multimeric protein assemblies are abundant in nature. Streptavidin is an attractive protein that provides a paradigm system to investigate the intra- and intermolecular interactions of multimeric protein complexes. Also, it offers a versatile tool for biotechnological applications. Here, we present two apo-streptavidin structures, the first one is an ambient temperature Serial Femtosecond X-ray crystal (Apo-SFX) structure at 1.7 angstrom resolution and the second one is a cryogenic crystal structure (Apo-Cryo) at 1.1 angstrom resolution. These structures are mostly in agreement with previous structural data. Combined with computational analysis, these structures provide invaluable information about structural dynamics of apo streptavidin. Collectively, these data further reveal a novel cooperative allostery of streptavidin which binds to substrate via water molecules that provide a polar interaction network and mimics the substrate biotin which displays one of the strongest affinities found in nature., National Science Foundation (NSF) Science and Technology Centers; 2232 International Fellowship for Outstanding Researchers Program; 1001 Scientific and Technological Research Projects Funding Program; Scientific and Technological Research Council of Turkey (TÜBİTAK); U.S. Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences (OBES); National Institutes of Health, National Institute of General Medical Sciences (NIGMS)

Published
2022

13. Near-physiological-temperature serial crystallography reveals conformations of SARS-CoV-2 main protease active site for improved drug repurposing

Author

Durdagi, Serdar, primary, Dağ, Çağdaş, additional, Dogan, Berna, additional, Yigin, Merve, additional, Avsar, Timucin, additional, Buyukdag, Cengizhan, additional, Erol, Ismail, additional, Ertem, Fatma Betul, additional, Calis, Seyma, additional, Yildirim, Gunseli, additional, Orhan, Muge D., additional, Guven, Omur, additional, Aksoydan, Busecan, additional, Destan, Ebru, additional, Sahin, Kader, additional, Besler, Sabri O., additional, Oktay, Lalehan, additional, Shafiei, Alaleh, additional, Tolu, Ilayda, additional, Ayan, Esra, additional, Yuksel, Busra, additional, Peksen, Ayse B., additional, Gocenler, Oktay, additional, Yucel, Ali D., additional, Can, Ozgur, additional, Ozabrahamyan, Serena, additional, Olkan, Alpsu, additional, Erdemoglu, Ece, additional, Aksit, Fulya, additional, Tanisali, Gokhan, additional, Yefanov, Oleksandr M., additional, Barty, Anton, additional, Tolstikova, Alexandra, additional, Ketawala, Gihan K., additional, Botha, Sabine, additional, Dao, E. Han, additional, Hayes, Brandon, additional, Liang, Mengning, additional, Seaberg, Matthew H., additional, Hunter, Mark S., additional, Batyuk, Alex, additional, Mariani, Valerio, additional, Su, Zhen, additional, Poitevin, Frederic, additional, Yoon, Chun Hong, additional, Kupitz, Christopher, additional, Sierra, Raymond G., additional, Snell, Edward H., additional, and DeMirci, Hasan, additional

Published
2021
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14. Cooperative Allostery and Structural Dynamics of Streptavidin at Cryogenic- and Ambient-temperature

Author

Ayan, Esra, primary, Yuksel, Busra, additional, Destan, Ebru, additional, Ertem, Fatma Betul, additional, Yildirim, Gunseli, additional, Eren, Meryem, additional, Yefanov, Oleksandr M., additional, Barty, Anton, additional, Tolstikova, Alexandra, additional, Ketawala, Gihan K., additional, Botha, Sabine, additional, Dao, E. Han, additional, Hayes, Brandon, additional, Liang, Mengning, additional, Seaberg, Matthew H., additional, Hunter, Mark S., additional, Batyuk, Alex, additional, Mariani, Valerio, additional, Su, Zhen, additional, Poitevin, Frederic, additional, Yoon, Chun Hong, additional, Kupitz, Christopher, additional, Cohen, Aina, additional, Doukov, Tzanko, additional, Sierra, Raymond G., additional, Dağ, Çağdaş, additional, and DeMirci, Hasan, additional

Published
2021
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15. Pink-beam serial femtosecond crystallography for accurate structure-factor determination at an X-ray free-electron laser

Author

Nass, Karol, primary, Bacellar, Camila, additional, Cirelli, Claudio, additional, Dworkowski, Florian, additional, Gevorkov, Yaroslav, additional, James, Daniel, additional, Johnson, Philip J. M., additional, Kekilli, Demet, additional, Knopp, Gregor, additional, Martiel, Isabelle, additional, Ozerov, Dmitry, additional, Tolstikova, Alexandra, additional, Vera, Laura, additional, Weinert, Tobias, additional, Yefanov, Oleksandr, additional, Standfuss, Jörg, additional, Reiche, Sven, additional, and Milne, Christopher J., additional

Published
2021
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16. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

Author

Günther, Sebastian, Reinke, Patrick Y. A., Fernández-García, Yaiza, Lieske, Julia, Lane, Thomas J., Ginn, Helen M., Koua, Faisal H. M., Ehrt, Christiane, Ewert, Wiebke, Oberthuer, Dominik, Yefanov, Oleksandr, Meier, Susanne, Lorenzen, Kristina, Krichel, Boris, Kopicki, Janine-Denise, Gelisio, Luca, Brehm, Wolfgang, Dunkel, Ilona, Seychell, Brandon, Gieseler, Henry, Norton-Baker, Brenna, Escudero-Pérez, Beatriz, Domaracky, Martin, Saouane, Sofiane, Tolstikova, Alexandra, White, Thomas A., Hänle, Anna, Groessler, Michael, Fleckenstein, Holger, Trost, Fabian, Galchenkova, Marina, Gevorkov, Yaroslav, Li, Chufeng, Awel, Salah, Peck, Ariana, Barthelmess, Miriam, Schlünzen, Frank, Lourdu Xavier, P., Werner, Nadine, Andaleeb, Hina, Ullah, Najeeb, Falke, Sven, Srinivasan, Vasundara, França, Bruno Alves, Schwinzer, Martin, Brognaro, Hévila, Rogers, Cromarte, Melo, Diogo, Zaitseva-Doyle, Joanna J., Knoska, Juraj, Peña-Murillo, Gisel E., Mashhour, Aida Rahmani, Hennicke, Vincent, Fischer, Pontus, Hakanpää, Johanna, Meyer, Jan, Gribbon, Philip, Ellinger, Bernhard, Kuzikov, Maria, Wolf, Markus, Beccari, Andrea R., Bourenkov, Gleb, von Stetten, David, Pompidor, Guillaume, Bento, Isabel, Panneerselvam, Saravanan, Karpics, Ivars, Schneider, Thomas R., Garcia-Alai, Maria Marta, Niebling, Stephan, Günther, Christian, Schmidt, Christina, Schubert, Robin, Han, Huijong, Boger, Juliane, Monteiro, Diana C. F., Zhang, Linlin, Sun, Xinyuanyuan, Pletzer-Zelgert, Jonathan, Wollenhaupt, Jan, Feiler, Christian G., Weiss, Manfred S., Schulz, Eike-Christian, Mehrabi, Pedram, Karničar, Katarina, Usenik, Aleksandra, Loboda, Jure, Tidow, Henning, Chari, Ashwin, Hilgenfeld, Rolf, Uetrecht, Charlotte, Cox, Russell, Zaliani, Andrea, Beck, Tobias, Rarey, Matthias, Günther, Stephan, Turk, Dusan, Hinrichs, Winfried, Chapman, Henry N., Pearson, Arwen R., Betzel, Christian, Meents, Alke, Günther, Sebastian, Reinke, Patrick Y. A., Fernández-García, Yaiza, Lieske, Julia, Lane, Thomas J., Ginn, Helen M., Koua, Faisal H. M., Ehrt, Christiane, Ewert, Wiebke, Oberthuer, Dominik, Yefanov, Oleksandr, Meier, Susanne, Lorenzen, Kristina, Krichel, Boris, Kopicki, Janine-Denise, Gelisio, Luca, Brehm, Wolfgang, Dunkel, Ilona, Seychell, Brandon, Gieseler, Henry, Norton-Baker, Brenna, Escudero-Pérez, Beatriz, Domaracky, Martin, Saouane, Sofiane, Tolstikova, Alexandra, White, Thomas A., Hänle, Anna, Groessler, Michael, Fleckenstein, Holger, Trost, Fabian, Galchenkova, Marina, Gevorkov, Yaroslav, Li, Chufeng, Awel, Salah, Peck, Ariana, Barthelmess, Miriam, Schlünzen, Frank, Lourdu Xavier, P., Werner, Nadine, Andaleeb, Hina, Ullah, Najeeb, Falke, Sven, Srinivasan, Vasundara, França, Bruno Alves, Schwinzer, Martin, Brognaro, Hévila, Rogers, Cromarte, Melo, Diogo, Zaitseva-Doyle, Joanna J., Knoska, Juraj, Peña-Murillo, Gisel E., Mashhour, Aida Rahmani, Hennicke, Vincent, Fischer, Pontus, Hakanpää, Johanna, Meyer, Jan, Gribbon, Philip, Ellinger, Bernhard, Kuzikov, Maria, Wolf, Markus, Beccari, Andrea R., Bourenkov, Gleb, von Stetten, David, Pompidor, Guillaume, Bento, Isabel, Panneerselvam, Saravanan, Karpics, Ivars, Schneider, Thomas R., Garcia-Alai, Maria Marta, Niebling, Stephan, Günther, Christian, Schmidt, Christina, Schubert, Robin, Han, Huijong, Boger, Juliane, Monteiro, Diana C. F., Zhang, Linlin, Sun, Xinyuanyuan, Pletzer-Zelgert, Jonathan, Wollenhaupt, Jan, Feiler, Christian G., Weiss, Manfred S., Schulz, Eike-Christian, Mehrabi, Pedram, Karničar, Katarina, Usenik, Aleksandra, Loboda, Jure, Tidow, Henning, Chari, Ashwin, Hilgenfeld, Rolf, Uetrecht, Charlotte, Cox, Russell, Zaliani, Andrea, Beck, Tobias, Rarey, Matthias, Günther, Stephan, Turk, Dusan, Hinrichs, Winfried, Chapman, Henry N., Pearson, Arwen R., Betzel, Christian, and Meents, Alke

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 alreadyapproved 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 nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

Published
2021

17. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

Author

Günther, Sebastian, primary, Reinke, Patrick Y. A., additional, Fernández-García, Yaiza, additional, Lieske, Julia, additional, Lane, Thomas J., additional, Ginn, Helen M., additional, Koua, Faisal H. M., additional, Ehrt, Christiane, additional, Ewert, Wiebke, additional, Oberthuer, Dominik, additional, Yefanov, Oleksandr, additional, Meier, Susanne, additional, Lorenzen, Kristina, additional, Krichel, Boris, additional, Kopicki, Janine-Denise, additional, Gelisio, Luca, additional, Brehm, Wolfgang, additional, Dunkel, Ilona, additional, Seychell, Brandon, additional, Gieseler, Henry, additional, Norton-Baker, Brenna, additional, Escudero-Pérez, Beatriz, additional, Domaracky, Martin, additional, Saouane, Sofiane, additional, Tolstikova, Alexandra, additional, White, Thomas A., additional, Hänle, Anna, additional, Groessler, Michael, additional, Fleckenstein, Holger, additional, Trost, Fabian, additional, Galchenkova, Marina, additional, Gevorkov, Yaroslav, additional, Li, Chufeng, additional, Awel, Salah, additional, Peck, Ariana, additional, Barthelmess, Miriam, additional, Schlünzen, Frank, additional, Lourdu Xavier, P., additional, Werner, Nadine, additional, Andaleeb, Hina, additional, Ullah, Najeeb, additional, Falke, Sven, additional, Srinivasan, Vasundara, additional, França, Bruno Alves, additional, Schwinzer, Martin, additional, Brognaro, Hévila, additional, Rogers, Cromarte, additional, Melo, Diogo, additional, Zaitseva-Doyle, Joanna J., additional, Knoska, Juraj, additional, Peña-Murillo, Gisel E., additional, Mashhour, Aida Rahmani, additional, Hennicke, Vincent, additional, Fischer, Pontus, additional, Hakanpää, Johanna, additional, Meyer, Jan, additional, Gribbon, Philip, additional, Ellinger, Bernhard, additional, Kuzikov, Maria, additional, Wolf, Markus, additional, Beccari, Andrea R., additional, Bourenkov, Gleb, additional, von Stetten, David, additional, Pompidor, Guillaume, additional, Bento, Isabel, additional, Panneerselvam, Saravanan, additional, Karpics, Ivars, additional, Schneider, Thomas R., additional, Garcia-Alai, Maria Marta, additional, Niebling, Stephan, additional, Günther, Christian, additional, Schmidt, Christina, additional, Schubert, Robin, additional, Han, Huijong, additional, Boger, Juliane, additional, Monteiro, Diana C. F., additional, Zhang, Linlin, additional, Sun, Xinyuanyuan, additional, Pletzer-Zelgert, Jonathan, additional, Wollenhaupt, Jan, additional, Feiler, Christian G., additional, Weiss, Manfred S., additional, Schulz, Eike-Christian, additional, Mehrabi, Pedram, additional, Karničar, Katarina, additional, Usenik, Aleksandra, additional, Loboda, Jure, additional, Tidow, Henning, additional, Chari, Ashwin, additional, Hilgenfeld, Rolf, additional, Uetrecht, Charlotte, additional, Cox, Russell, additional, Zaliani, Andrea, additional, Beck, Tobias, additional, Rarey, Matthias, additional, Günther, Stephan, additional, Turk, Dusan, additional, Hinrichs, Winfried, additional, Chapman, Henry N., additional, Pearson, Arwen R., additional, Betzel, Christian, additional, and Meents, Alke, additional

Published
2021
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18. Direct Observation of the Mechanism of Antibiotic Resistance by Mix-and-Inject at the European XFEL

Author

Pandey, Suraj, Bean, Richard, Hunter, Mark, Abdellatif, Mohamed H., Bajt, Saša, Bondar, Valerii, Echelmeier, Austin, Doppler, Diandra, Emons, Moritz, Frank, Matthias, Fromme, Raimund, Gevorkov, Yaroslav, Sato, Tokushi, Giovanetti, Gabriele, Jiang, Man, Kim, Daihyun, Kim, Yoonhee, Kirkwood, Henry, Klimovskaia, Anna, Knoska, Juraj, Koua, Faisal H. M., Letrun, Romain, Lisova, Stella, Poudyal, Ishwor, Maia, Luis, Mazalova, Victoria, Meza, Domingo, Michelat, Thomas, Ourmazd, Abbas, Palmer, Guido, Ramilli, Marco, Schubert, Robin, Schwander, Peter, Silenzi, Alessandro, Bielecki, Johan, Sztuk-Dambietz, Jolanta, Tolstikova, Alexandra, Chapman, Henry N., Ros, Alexandra, Barty, Anton, Fromme, Petra, Mancuso, Adrian P., Schmidt, Marius, Cruz Villarreal, Jorvani, Yefanov, Oleksandr, Mariani, Valerio, White, Thomas A., and Kupitz, Christopher

Subjects
Enzyme substrate complex, Millisecond, Materials science, Bacterial antibiotic resistance, Chemical physics, Atomic resolution, Direct observation, Substrate (chemistry), Time resolution, ddc:610, Ultrashort pulse
Abstract

In this study, we follow the diffusion and buildup of occupancy of the substrate ceftriaxone inM. tuberculosisβ-lactamase BlaC microcrystals by structural analysis of the enzyme substrate complex at single millisecond time resolution. We also show the binding and the reaction of an inhibitor, sulbactam, on a slower millisecond time scale. We use the ‘mix-and-inject’ technique to initiate these reactions by diffusion, and determine the resulting structures by serial crystallography using ultrafast, intense X-ray pulses from the European XFEL (EuXFEL) arriving at MHz repetition rates. Here, we show how to use the EuXFEL pulse structure to dramatically increase the size of the data set and thereby the quality and time resolution of “molecular movies” which unravel ligand binding and enzymatically catalyzed reactions. This shows the great potential for the EuXFEL as a tool for biomedically relevant research, particularly, as shown here, for investigating bacterial antibiotic resistance.One Sentence SummaryDirect observation of fast ligand binding in a biomedically relevant enzyme at near atomic resolution with MHz X-ray pulses at the European XFEL.

Published
2020

19. Femtosecond X-ray diffraction from an aerosolized beam of protein nanocrystals

Author

Awel, Salah, Kirian, Richard A., Adriano, Luigi, Tolstikova, Alexandra, Paulraj, Lourdu Xavier, Yefanov, Oleksandr, Aquila, Andrew, Barty, Anton, Roy-Chowdhury, Shatabdi, Hunter, Mark S., James, Daniel, Robinson, Joseph S., Wiedorn, Max O., Weierstall, Uwe, Rode, Andrei, Bajt, Saša, Küpper, Jochen, Chapman, Henry N., Beyerlein, Kenneth, Roth, Nils, Horke, Daniel, Oberthür, Dominik, Knoska, Juraj, Mariani, Valerio, and Morgan, Andrew

Subjects
nanocrystals, Biological Physics (physics.bio-ph), ddc:540, Physics::Optics, FOS: Physical sciences, ddc:530, Physics - Biological Physics, Research Papers, aerosols, X-ray diffraction
Abstract

A new particle-injection approach is demonstrated that achieves very low background in the measurement of diffraction from macromolecular nanocrystals by using an aerosol-focusing injector with an X-ray free-electron laser., High-resolution Bragg diffraction from aerosolized single granulovirus nanocrystals using an X-ray free-electron laser is demonstrated. The outer dimensions of the in-vacuum aerosol injector components are identical to conventional liquid-microjet nozzles used in serial diffraction experiments, which allows the injector to be utilized with standard mountings. As compared with liquid-jet injection, the X-ray scattering background is reduced by several orders of magnitude by the use of helium carrier gas rather than liquid. Such reduction is required for diffraction measurements of small macromolecular nanocrystals and single particles. High particle speeds are achieved, making the approach suitable for use at upcoming high-repetition-rate facilities.

Published
2018

20. Direct Observation of the Mechanism of Antibiotic Resistance by Mix-and-Inject at the European XFEL

Author

Pandey, Suraj, primary, Calvey, George, additional, Katz, Andrea M., additional, Malla, Tek Narsingh, additional, Koua, Faisal H. M., additional, Martin-Garcia, Jose M., additional, Poudyal, Ishwor, additional, Yang, Jay-How, additional, Vakili, Mohammad, additional, Yefanov, Oleksandr, additional, Zielinski, Kara A., additional, Bajt, Saša, additional, Awel, Salah, additional, Dörner, Katerina, additional, Frank, Matthias, additional, Gelisio, Luca, additional, Jernigan, Rebecca, additional, Kirkwood, Henry, additional, Kloos, Marco, additional, Koliyadu, Jayanath, additional, Mariani, Valerio, additional, Miller, Mitchell D., additional, Mills, Grant, additional, Nelson, Garrett, additional, Olmos, Jose L., additional, Sadri, Alireza, additional, Sato, Tokushi, additional, Tolstikova, Alexandra, additional, Xu, Weijun, additional, Ourmazd, Abbas, additional, Spence, John H. C., additional, Schwander, Peter, additional, Barty, Anton, additional, Chapman, Henry N., additional, Fromme, Petra, additional, Mancuso, Adrian P., additional, Phillips, George N., additional, Bean, Richard, additional, Pollack, Lois, additional, and Schmidt, Marius, additional

Published
2020
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21. Inhibition of SARS-CoV-2 main protease by allosteric drug-binding

Author

Günther, Sebastian, primary, Reinke, Patrick Y. A., additional, Fernández-García, Yaiza, additional, Lieske, Julia, additional, Lane, Thomas J., additional, Ginn, Helen M., additional, Koua, Faisal H. M., additional, Ehrt, Christiane, additional, Ewert, Wiebke, additional, Oberthuer, Dominik, additional, Yefanov, Oleksandr, additional, Meier, Susanne, additional, Lorenzen, Kristina, additional, Krichel, Boris, additional, Kopicki, Janine-Denise, additional, Gelisio, Luca, additional, Brehm, Wolfgang, additional, Dunkel, Ilona, additional, Seychell, Brandon, additional, Gieseler, Henry, additional, Norton-Baker, Brenna, additional, Escudero-Pérez, Beatriz, additional, Domaracky, Martin, additional, Saouane, Sofiane, additional, Tolstikova, Alexandra, additional, White, Thomas A., additional, Hänle, Anna, additional, Groessler, Michael, additional, Fleckenstein, Holger, additional, Trost, Fabian, additional, Galchenkova, Marina, additional, Gevorkov, Yaroslav, additional, Li, Chufeng, additional, Awel, Salah, additional, Peck, Ariana, additional, Barthelmess, Miriam, additional, Schlünzen, Frank, additional, Xavier, P. Lourdu, additional, Werner, Nadine, additional, Andaleeb, Hina, additional, Ullah, Najeeb, additional, Falke, Sven, additional, Srinivasan, Vasundara, additional, Franca, Bruno Alves, additional, Schwinzer, Martin, additional, Brognaro, Hévila, additional, Rogers, Cromarte, additional, Melo, Diogo, additional, Zaitsev-Doyle, Jo J., additional, Knoska, Juraj, additional, Peña Murillo, Gisel E., additional, Mashhour, Aida Rahmani, additional, Guicking, Filip, additional, Hennicke, Vincent, additional, Fischer, Pontus, additional, Hakanpää, Johanna, additional, Meyer, Jan, additional, Gribbon, Phil, additional, Ellinger, Bernhard, additional, Kuzikov, Maria, additional, Wolf, Markus, additional, Beccari, Andrea R., additional, Bourenkov, Gleb, additional, Stetten, David von, additional, Pompidor, Guillaume, additional, Bento, Isabel, additional, Panneerselvam, Saravanan, additional, Karpics, Ivars, additional, Schneider, Thomas R., additional, Garcia Alai, Maria Marta, additional, Niebling, Stephan, additional, Günther, Christian, additional, Schmidt, Christina, additional, Schubert, Robin, additional, Han, Huijong, additional, Boger, Juliane, additional, Monteiro, Diana C. F., additional, Zhang, Linlin, additional, Sun, Xinyuanyuan, additional, Pletzer-Zelgert, Jonathan, additional, Wollenhaupt, Jan, additional, Feiler, Christian G., additional, Weiss, Manfred S., additional, Schulz, Eike-Christian, additional, Mehrabi, Pedram, additional, Karničar, Katarina, additional, Usenik, Aleksandra, additional, Loboda, Jure, additional, Tidow, Henning, additional, Chari, Ashwin, additional, Hilgenfeld, Rolf, additional, Uetrecht, Charlotte, additional, Cox, Russell, additional, Zaliani, Andrea, additional, Beck, Tobias, additional, Rarey, Matthias, additional, Günther, Stephan, additional, Turk, Dusan, additional, Hinrichs, Winfried, additional, Chapman, Henry N., additional, Pearson, Arwen R., additional, Betzel, Christian, additional, and Meents, Alke, additional

Published
2020
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22. Near-Physiological-Temperature Serial Femtosecond X-ray Crystallography Reveals Novel Conformations of SARS-CoV-2 Main Protease Active Site for Improved Drug Repurposing

Author

Durdagi, Serdar, primary, Dag, Cagdas, additional, Dogan, Berna, additional, Yigin, Merve, additional, Avsar, Timucin, additional, Buyukdag, Cengizhan, additional, Erol, Ismail, additional, Ertem, Betul, additional, Calis, Seyma, additional, Yildirim, Gunseli, additional, Orhan, Muge D., additional, Guven, Omur, additional, Aksoydan, Busecan, additional, Destan, Ebru, additional, Sahin, Kader, additional, Besler, Sabri O., additional, Oktay, Lalehan, additional, Shafiei, Alaleh, additional, Tolu, Ilayda, additional, Ayan, Esra, additional, Yuksel, Busra, additional, Peksen, Ayse B., additional, Gocenler, Oktay, additional, Yucel, Ali D., additional, Can, Ozgur, additional, Ozabrahamyan, Serena, additional, Olkan, Alpsu, additional, Erdemoglu, Ece, additional, Aksit, Fulya, additional, Tanisali, Gokhan, additional, Yefanov, Oleksandr M., additional, Barty, Anton, additional, Tolstikova, Alexandra, additional, Ketawala, Gihan K., additional, Botha, Sabine, additional, Dao, E. Han, additional, Hayes, Brandon, additional, Liang, Mengning, additional, Seaberg, Matthew H., additional, Hunter, Mark S., additional, Batyuk, Alex, additional, Mariani, Valerio, additional, Su, Zhen, additional, Poitevin, Frederic, additional, Yoon, Chun Hong, additional, Kupitz, Christopher, additional, Sierra, Raymond G., additional, Snell, Edward, additional, and DeMirci, Hasan, additional

Published
2020
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23. Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

Author

Günther, Sebastian, primary, Reinke, Patrick Y. A., additional, Oberthuer, Dominik, additional, Yefanov, Oleksandr, additional, Ginn, Helen, additional, Meier, Susanne, additional, Lane, Thomas J., additional, Lorenzen, Kristina, additional, Gelisio, Luca, additional, Brehm, Wolfgang, additional, Dunkel, Illona, additional, Domaracky, Martin, additional, Saouane, Sofiane, additional, Lieske, Julia, additional, Ehrt, Christiane, additional, Koua, Faisal, additional, Tolstikova, Alexandra, additional, White, Thomas A., additional, Groessler, Michael, additional, Fleckenstein, Holger, additional, Trost, Fabian, additional, Galchenkova, Marina, additional, Gevorkov, Yaroslav, additional, Li, Chufeng, additional, Awel, Salah, additional, Peck, Ariana, additional, Xavier, P. Lourdu, additional, Barthelmess, Miriam, additional, Schlünzen, Frank, additional, Werner, Nadine, additional, Andaleeb, Hina, additional, Ullah, Najeeb, additional, Falke, Sven, additional, Franca, Bruno Alves, additional, Schwinzer, Martin, additional, Brognaro, Hévila, additional, Seychell, Brandon, additional, Gieseler, Henry, additional, Melo, Diogo, additional, Zaitsev-Doyle, Jo J., additional, Norton-Baker, Brenna, additional, Knoska, Juraj, additional, Esperanza, Gisel, additional, Mashhour, Aida Rahmani, additional, Guicking, Filip, additional, Hennicke, Vincent, additional, Fischer, Pontus, additional, Rogers, Cromarte, additional, Monteiro, Diana C. F., additional, Hakanpää, Johanna, additional, Meyer, Jan, additional, Noei, Heshmat, additional, Gribbon, Phil, additional, Ellinger, Bernhard, additional, Kuzikov, Maria, additional, Wolf, Markus, additional, Zhang, Linlin, additional, Sun, Xinyuanyuan, additional, Pletzer-Zelgert, Jonathan, additional, Wollenhaupt, Jan, additional, Feiler, Christian, additional, Weiss, Manfred, additional, Schulz, Eike-Christian, additional, Mehrabi, Pedram, additional, Schmidt, Christina, additional, Schubert, Robin, additional, Han, Huijong, additional, Krichel, Boris, additional, Fernández-García, Yaiza, additional, Escudero-Pérez, Beatriz, additional, Günther, Stephan, additional, Turk, Dusan, additional, Uetrecht, Charlotte, additional, Beck, Tobias, additional, Tidow, Henning, additional, Chari, Ashwin, additional, Zaliani, Andrea, additional, Rarey, Matthias, additional, Cox, Russell, additional, Hilgenfeld, Rolf, additional, Chapman, Henry N., additional, Pearson, Arwen R., additional, Betzel, Christian, additional, and Meents, Alke, additional

Published
2020
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24. Time-resolved serial femtosecond crystallography at the European XFEL

Author

Pandey, Suraj, primary, Bean, Richard, additional, Sato, Tokushi, additional, Poudyal, Ishwor, additional, Bielecki, Johan, additional, Cruz Villarreal, Jorvani, additional, Yefanov, Oleksandr, additional, Mariani, Valerio, additional, White, Thomas A., additional, Kupitz, Christopher, additional, Hunter, Mark, additional, Abdellatif, Mohamed H., additional, Bajt, Saša, additional, Bondar, Valerii, additional, Echelmeier, Austin, additional, Doppler, Diandra, additional, Emons, Moritz, additional, Frank, Matthias, additional, Fromme, Raimund, additional, Gevorkov, Yaroslav, additional, Giovanetti, Gabriele, additional, Jiang, Man, additional, Kim, Daihyun, additional, Kim, Yoonhee, additional, Kirkwood, Henry, additional, Klimovskaia, Anna, additional, Knoska, Juraj, additional, Koua, Faisal H. M., additional, Letrun, Romain, additional, Lisova, Stella, additional, Maia, Luis, additional, Mazalova, Victoria, additional, Meza, Domingo, additional, Michelat, Thomas, additional, Ourmazd, Abbas, additional, Palmer, Guido, additional, Ramilli, Marco, additional, Schubert, Robin, additional, Schwander, Peter, additional, Silenzi, Alessandro, additional, Sztuk-Dambietz, Jolanta, additional, Tolstikova, Alexandra, additional, Chapman, Henry N., additional, Ros, Alexandra, additional, Barty, Anton, additional, Fromme, Petra, additional, Mancuso, Adrian P., additional, and Schmidt, Marius, additional

Published
2019
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25. Recent developments in $Cryst$FEL

Author

White, Thomas, Mariani, Valerio, Brehm, Wolfgang, Yefanov, Oleksandr, Barty, Anton, Beyerlein, Kenneth, Chervinskii, Fedor, Galli, Lorenzo, Gati, Cornelius, Nakane, Takanori, Tolstikova, Alexandra, Yamashita, Keitaro, Yoon, Chun Hong, Diederichs, Kay, and Chapman, Henry N.

Subjects
ddc:540
Abstract

Journal of applied crystallography 49(2), 680 - 689(2016). doi:10.1107/S1600576716004751, $Cryst$FEL is a suite of programs for processing data from `serial crystallography' experiments, which are usually performed using X-ray free-electron lasers (FELs) but also increasingly with other X-ray sources. The $Cryst$FEL software suite has been under development since 2009, just before the first hard FEL experiments were performed, and has been significantly updated and improved since then. This article describes the most important improvements which have been made to $Cryst$FEL since the first release version. These changes include the addition of new programs to the suite, the ability to resolve `indexing ambiguities' and several ways to improve the quality of the integrated data by more accurately modelling the underlying diffraction physics., Published by Munksgaard, Copenhagen

Published
2016
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26. Structural basis for selectivity and diversity in angiotensin II receptors

Author

Zhang, Haitao, primary, Han, Gye Won, additional, Batyuk, Alexander, additional, Ishchenko, Andrii, additional, White, Kate L., additional, Patel, Nilkanth, additional, Sadybekov, Anastasiia, additional, Zamlynny, Beata, additional, Rudd, Michael T., additional, Hollenstein, Kaspar, additional, Tolstikova, Alexandra, additional, White, Thomas A., additional, Hunter, Mark S., additional, Weierstall, Uwe, additional, Liu, Wei, additional, Babaoglu, Kerim, additional, Moore, Eric L., additional, Katz, Ryan D., additional, Shipman, Jennifer M., additional, Garcia-Calvo, Margarita, additional, Sharma, Sujata, additional, Sheth, Payal, additional, Soisson, Stephen M., additional, Stevens, Raymond C., additional, Katritch, Vsevolod, additional, and Cherezov, Vadim, additional

Published
2017
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27. Recent developments in CrystFEL

Author

White, Thomas A., primary, Mariani, Valerio, additional, Brehm, Wolfgang, additional, Yefanov, Oleksandr, additional, Barty, Anton, additional, Beyerlein, Kenneth R., additional, Chervinskii, Fedor, additional, Galli, Lorenzo, additional, Gati, Cornelius, additional, Nakane, Takanori, additional, Tolstikova, Alexandra, additional, Yamashita, Keitaro, additional, Yoon, Chun Hong, additional, Diederichs, Kay, additional, and Chapman, Henry N., additional

Published
2016
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29. Observation of substrate diffusion and ligand binding in enzyme crystals using high-repetition-rate mix-and-inject serial crystallography

Author

Pandey, Suraj, Calvey, George, Katz, Andrea M., Malla, Tek Narsingh, Koua, Faisal H. M., Martin-Garcia, Jose M., Poudyal, Ishwor, Yang, Jay-How, Vakili, Mohammad, Yefanov, Oleksandr, Zielinski, Kara A., Bajt, Sasa, Awel, Salah, Doerner, Katarina, Frank, Matthias, Gelisio, Luca, Jernigan, Rebecca, Kirkwood, Henry, Kloos, Marco, Koliyadu, Jayanath, Mariani, Valerio, Miller, Mitchell D., Mills, Grant, Nelson, Garrett, Olmos, Jose L., Sadri, Alireza, Sato, Tokushi, Tolstikova, Alexandra, Xu, Weijun, Ourmazd, Abbas, Spence, John C. H., Schwander, Peter, Barty, Anton, Chapman, Henry N., Fromme, Petra, Mancuso, Adrian P., Phillips, George N., Bean, Richard, Pollack, Lois, and Schmidt, Marius

Subjects
3. Good health
Abstract

IUCrJ 8(6), 878 - 895 (2021). doi:10.1107/S2052252521008125, Here, we illustrate what happens inside the catalytic cleft of an enzyme when substrate or ligand binds on single-millisecond timescales. The initial phase of the enzymatic cycle is observed with near-atomic resolution using the most advanced X-ray source currently available: the European XFEL (EuXFEL). The high repetition rate of the EuXFEL combined with our mix-and-inject technology enables the initial phase of ceftriaxone binding to the Mycobacterium tuberculosis ��-lactamase to be followed using time-resolved crystallography in real time. It is shown how a diffusion coefficient in enzyme crystals can be derived directly from the X-ray data, enabling the determination of ligand and enzyme���ligand concentrations at any position in the crystal volume as a function of time. In addition, the structure of the irreversible inhibitor sulbactam bound to the enzyme at a 66 ms time delay after mixing is described. This demonstrates that the EuXFEL can be used as an important tool for biomedically relevant research., Published by Chester

30. Femtosecond X-ray diffraction from an aerosolized beam of protein nanocrystals

Author

Awel, Salah, Kirian, Richard A., Wiedorn, Max O., Beyerlein, Kenneth R., Roth, Nils, Horke, Daniel A., Oberthür, Dominik, Knoska, Juraj, Mariani, Valerio, Morgan, Andrew, Adriano, Luigi, Tolstikova, Alexandra, Xavier, P. Lourdu, Yefanov, Oleksandr, Aquila, Andrew, Barty, Anton, Roy-Chowdhury, Shatabdi, Hunter, Mark S., James, Daniel, Robinson, Joseph S., Weierstall, Uwe, Rode, Andrei V., Bajt, Saša, Küpper, Jochen, and Chapman, Henry N.

Subjects
3. Good health
Abstract

Journal of applied crystallography 51(1), 133 - 139 (2018). doi:10.1107/S1600576717018131, High-resolution Bragg diffraction from aerosolized single granulovirus nano-crystals using an X-ray free-electron laser is demonstrated. The outerdimensions of the in-vacuum aerosol injector components are identical toconventional liquid-microjet nozzles used in serial diffraction experiments,which allows the injector to be utilized with standard mountings. As comparedwith liquid-jet injection, the X-ray scattering background is reduced by severalorders of magnitude by the use of helium carrier gas rather than liquid. Suchreduction is required for diffraction measurements of small macromolecularnanocrystals and single particles. High particle speeds are achieved, making theapproach suitable for use at upcoming high-repetition-rate facilities., Published by Munksgaard, Copenhagen

31. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

Author

Günther, Sebastian, Reinke, Patrick Y. A., Fernández-García, Yaiza, Lieske, Julia, Lane, Thomas J., Ginn, Helen M., Koua, Faisal H. M., Ehrt, Christiane, Ewert, Wiebke, Oberthuer, Dominik, Yefanov, Oleksandr, Meier, Susanne, Lorenzen, Kristina, Krichel, Boris, Kopicki, Janine-Denise, Gelisio, Luca, Brehm, Wolfgang, Dunkel, Ilona, Seychell, Brandon, Gieseler, Henry, Norton-Baker, Brenna, Escudero-Pérez, Beatriz, Domaracky, Martin, Saouane, Sofiane, Tolstikova, Alexandra, White, Thomas A., Hänle, Anna, Groessler, Michael, Fleckenstein, Holger, Trost, Fabian, Galchenkova, Marina, Gevorkov, Yaroslav, Li, Chufeng, Awel, Salah, Peck, Ariana, Barthelmess, Miriam, Schluenzen, Frank, Lourdu Xavier, Paulraj, Werner, Nadine, Andaleeb, Hina, Ullah, Najeeb, Falke, Sven, Srinivasan, Vasundara, França, Bruno Alves, Schwinzer, Martin, Brognaro, Hévila, Rogers, Cromarte, Melo, Diogo, Zaitseva-Doyle, Joanna J., Knoska, Juraj, Peña-Murillo, Gisel E., Mashhour, Aida Rahmani, Hennicke, Vincent, Fischer, Pontus, Hakanpää, Johanna, Meyer, Jan, Gribbon, Philip, Ellinger, Bernhard, Kuzikov, Maria, Wolf, Markus, Beccari, Andrea R., Bourenkov, Gleb, Von Stetten, David, Pompidor, Guillaume, Bento, Isabel, Panneerselvam, Saravanan, Karpics, Ivars, Schneider, Thomas R., Garcia-Alai, Maria Marta, Niebling, Stephan, Guenther, Christian, Schmidt, Christina, Schubert, Robin, Han, Huijong, Boger, Juliane, Monteiro, Diana C. F., Zhang, Linlin, Sun, Xinyuanyuan, Pletzer-Zelgert, Jonathan, Wollenhaupt, Jan, Feiler, Christian G., Weiss, Manfred S., Schulz, Eike-Christian, Mehrabi, Pedram, Karničar, Katarina, Usenik, Aleksandra, Loboda, Jure, Tidow, Henning, Chari, Ashwin, Hilgenfeld, Rolf, Uetrecht, Charlotte, Cox, Russell, Zaliani, Andrea, Beck, Tobias, Rarey, Matthias, Günther, Stephan, Turk, Dusan, Hinrichs, Winfried, Chapman, Henry N., Pearson, Arwen R., Betzel, Christian, and Meents, Alke

Subjects
3. Good health
Abstract

Science / Science now x, eabf7945 (1-11) (2021). doi:10.1126/science.abf7945, 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., Published by Assoc., Washington, DC

32. Inhibition of SARS-CoV-2 main protease by allosteric drug-binding

Author

Günther, Sebastian, Reinke, Patrick Y. A., Fernández-García, Yaiza, Lieske, Julia, Lane, Thomas J., Ginn, Helen M., Koua, Faisal H. M., Ehrt, Christiane, Ewert, Wiebke, Oberthuer, Dominik, Yefanov, Oleksandr, Meier, Susanne, Lorenzen, Kristina, Krichel, Boris, Kopicki, Janine-Denise, Gelisio, Luca, Brehm, Wolfgang, Dunkel, Ilona, Seychell, Brandon, Gieseler, Henry, Norton-Baker, Brenna, Escudero-Pérez, Beatriz, Domaracky, Martin, Saouane, Sofiane, Tolstikova, Alexandra, White, Thomas A., Hänle, Anna, Groessler, Michael, Fleckenstein, Holger, Trost, Fabian, Galchenkova, Marina, Gevorkov, Yaroslav, Li, Chufeng, Awel, Salah, Peck, Ariana, Barthelmess, Miriam, Schlünzen, Frank, Xavier, P. Lourdu, Werner, Nadine, Andaleeb, Hina, Ullah, Najeeb, Falke, Sven, Srinivasan, Vasundara, Franca, Bruno Alves, Schwinzer, Martin, Brognaro, Hévila, Rogers, Cromarte, Melo, Diogo, Zaitsev-Doyle, Jo J., Knoska, Juraj, Peña Murillo, Gisel E., Mashhour, Aida Rahmani, Guicking, Filip, Hennicke, Vincent, Fischer, Pontus, Hakanpää, Johanna, Meyer, Jan, Gribbon, Phil, Ellinger, Bernhard, Kuzikov, Maria, Wolf, Markus, Beccari, Andrea R., Bourenkov, Gleb, Stetten, David von, Pompidor, Guillaume, Bento, Isabel, Panneerselvam, Saravanan, Karpics, Ivars, Schneider, Thomas R., Garcia Alai, Maria Marta, Niebling, Stephan, Günther, Christian, Schmidt, Christina, Schubert, Robin, Han, Huijong, Boger, Juliane, Monteiro, Diana C. F., Zhang, Linlin, Sun, Xinyuanyuan, Pletzer-Zelgert, Jonathan, Wollenhaupt, Jan, Feiler, Christian G., Weiss, Manfred S., Schulz, Eike-Christian, Mehrabi, Pedram, Karničar, Katarina, Usenik, Aleksandra, Loboda, Jure, Tidow, Henning, Chari, Ashwin, Hilgenfeld, Rolf, Uetrecht, Charlotte, Cox, Russell, Zaliani, Andrea, Beck, Tobias, Rarey, Matthias, Günther, Stephan, Turk, Dusan, Hinrichs, Winfried, Chapman, Henry N., Pearson, Arwen R., Betzel, Christian, and Meents, Alke

Abstract

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for the virus replication and, thus, a potent drug target. 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 binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five 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. Competing Interest Statement

33. Cooperative allostery and structural dynamics of streptavidin at cryogenic- and ambient-temperature

Author

Esra Ayan, Busra Yuksel, Ebru Destan, Fatma Betul Ertem, Gunseli Yildirim, Meryem Eren, Oleksandr M. Yefanov, Anton Barty, Alexandra Tolstikova, Gihan K. Ketawala, Sabine Botha, E. Han Dao, Brandon Hayes, Mengning Liang, Matthew H. Seaberg, Mark S. Hunter, Alexander Batyuk, Valerio Mariani, Zhen Su, Frederic Poitevin, Chun Hong Yoon, Christopher Kupitz, Aina Cohen, Tzanko Doukov, Raymond G. Sierra, Çağdaş Dağ, Hasan DeMirci, Dağ, Çağdaş, Ayan, Esra, Yüksel, Büşra, Destan, Ebru, Ertem, Fatma Betül, Yıldırım, Günseli, Eren, Meryem, Demirci, Hasan (ORCID 0000-0002-9135-5397 & YÖK ID 307350), Yefanov, Oleksandr M., Barty, Anton, Tolstikova, Alexandra, Ketawala, Gihan K., Botha, Sabine, Dao, E. Han, Hayes, Brandon, Liang, Mengning, Seaberg, Matthew H., Hunter, Mark S., Batyuk, Alexander, Mariani, Valerio, Su, Zhen, Poitevin, Frederic, Yoon, Chun Hong, Kupitz, Christopher, Cohen, Aina, Doukov, Tzanko, Sierra, Raymond G., Graduate School of Sciences and Engineering, College of Engineering, and Department of Molecular Biology and Genetics

Subjects
Biology, Multidisciplinary sciences, genetic structures, QH301-705.5, Nanocrystallography, Temperature, Medicine (miscellaneous), General Biochemistry, Genetics and Molecular Biology, Article, Streptavidin, ddc:570, Enzyme mechanisms, Biology (General), General Agricultural and Biological Sciences
Abstract

Communications biology 5(1), 73 (2022). doi:10.1038/s42003-021-02903-7, Multimeric protein assemblies are abundant in nature. Streptavidin is an attractive protein that provides a paradigm system to investigate the intra- and intermolecular interactions of multimeric protein complexes. Also, it offers a versatile tool for biotechnological applications. Here, we present two apo-streptavidin structures, the first one is an ambient temperature Serial Femtosecond X-ray crystal (Apo-SFX) structure at 1.7 Å resolution and the second one is a cryogenic crystal structure (Apo-Cryo) at 1.1 Å resolution. These structures are mostly in agreement with previous structural data. Combined with computational analysis, these structures provide invaluable information about structural dynamics of apo streptavidin. Collectively, these data further reveal a novel cooperative allostery of streptavidin which binds to substrate via water molecules that provide a polar interaction network and mimics the substrate biotin which displays one of the strongest affinities found in nature., Published by Springer Nature, London

Published
2022

34. Heterogeneity in the M. tuberculosis β-Lactamase Inhibition by Sulbactam.

Author

Schmidt M, Malla TN, Zielinski K, Aldama L, Bajt S, Feliz D, Hayes B, Hunter M, Kupitz C, Lisova S, Knoska J, Martin-Garcia J, Mariani V, Pandey S, Poudyal I, Sierra R, Tolstikova A, Yefanov O, Yoon CH, Ourmazd A, Fromme P, Schwander P, Barty A, Chapman H, Stojković E, Batyuk A, Boutet S, Phillips G Jr, and Pollack L

Abstract

For decades, researchers have been determined to elucidate essential enzymatic functions on the atomic lengths scale by tracing atomic positions in real time. Our work builds on new possibilities unleashed by mix-and-inject serial crystallography (MISC) 1-5 at X-ray free electron laser facilities. In this approach, enzymatic reactions are triggered by mixing substrate or ligand solutions with enzyme microcrystals 6 . Here, we report in atomic detail and with millisecond time-resolution how the Mycobacterium tuberculosis enzyme BlaC is inhibited by sulbactam (SUB). Our results reveal ligand binding heterogeneity, ligand gating 7-9 , cooperativity, induced fit 10,11 and conformational selection 11-13 all from the same set of MISC data, detailing how SUB approaches the catalytic clefts and binds to the enzyme non-covalently before reacting to a trans- enamine. This was made possible in part by the application of the singular value decomposition 14 to the MISC data using a newly developed program that remains functional even if unit cell parameters change during the reaction.

Published
2023
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