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2. Investigations of the dynamics and mechanism of β-phosphoglucomutase

Author

Robertson, Angus and Waltho, Jonathan

Subjects
572.8
Abstract

This thesis uses a multidisciplinary approach of nuclear magnetic resonance (NMR) spectroscopy, Xray crystallography, and enzyme kinetics to further investigate how β-Phosphoglucomutase (βPGM; EC 5.4.2.6) , an archetypal phosphoryl transfer enzyme from the HAD superfamily, catalyses the inter-conversion of β-glucose 1-phosphate (βG1P) with glucose 6-phosphate (G6P) via a β-glucose 1,6-phosphate (βG16P) intermediate. The use of metal fluorides to mimic positions along the reaction coordinate of phosphoryl transfer enzymes has been well established and allows for a critical investigation of the the role of enzyme dynamics, electrostatics, conformation, and intrinsic organization of the enzyme in catalysis. In a series of papers, this thesis demonstrates several elements of how βPGM has evolved to perform its function. Firstly, mutation of the enzymatic general acid-base (GAB) allowed the investigation of native substrate in the active site of the enzyme. This ground state model was closed around the substrate, with transferring phosphate and nucleophile in van der Waals contact, but without overall transition state architecture. Furthermore, a weakened magnesium affinity in this ground state suggests a mechanism for dissociation of such a high affinity ligand, essential for efficient catalysis. Secondly, using the same GAB mutation, the role of proton transfer in phosphoryl transfer reactions is investigated in pre- and post- proton transfer models. Using a combination of NMR, X-ray crystallography and DFT calculation, it is determined that the proton transfer event is not synchronous with phosphorous transfer, and several key themes are elucidated; before, during, and after the chemical transfer. Each of which contribute to the capacity of βPGM to break and form phosphate monoester bonds on a viable timescale. Thirdly, a mechanism is presented to explain a previously modelled enzymatic lag phase prior to steady state catalysis. Mutation of a key arginine residue is sufficient to alleviate this lag phase and does not perturb the chemical step of the reaction which indicates that such perturbations are not transmitted through substrate to the catalytic center. Finally, it is observed that the phospho-enzyme state of βPGM, when compared to a specific phosphatase (phosphoserine phosphatase (PSP)), displays several features in order to stabilize the phospho-enzyme state that are not present in PSP. Together these features further describe how βPGM has evolved both specificity and to achieve high levels of catalytic rate enhancement.

Published
2018

3. Targeting the main protease (Mpro, nsp5) by growth of fragment scaffolds exploiting structure-based methodologies

Author

Altincekic, Nadide, Jores, Nathalie, Löhr, Frank, Richter, Christian, Ehrhardt, Claus, Blommers, Marcel J. J., Berg, Hannes, Öztürk, Sare, Gande, Santosh L., Linhard, Verena, Orts, Julien, Abi Saad, Marie Jose, Bütikofer, Matthias, Kaderli, Janina, Karlsson, B. Göran, Brath, Ulrika, Hedenström, Mattias, Gröbner, Gerhard, Sauer, Uwe H., Perrakis, Anastassis, Langer, Julian, Banci, Lucia, Cantini, Francesca, Fragai, Marco, Grifagni, Deborah, Barthel, Tatjana, Wollenhaupt, Jan, Weiss, Manfred S., Robertson, Angus, Bax, Adriaan, Sreeramulu, Sridhar, Schwalbe, Harald, Altincekic, Nadide, Jores, Nathalie, Löhr, Frank, Richter, Christian, Ehrhardt, Claus, Blommers, Marcel J. J., Berg, Hannes, Öztürk, Sare, Gande, Santosh L., Linhard, Verena, Orts, Julien, Abi Saad, Marie Jose, Bütikofer, Matthias, Kaderli, Janina, Karlsson, B. Göran, Brath, Ulrika, Hedenström, Mattias, Gröbner, Gerhard, Sauer, Uwe H., Perrakis, Anastassis, Langer, Julian, Banci, Lucia, Cantini, Francesca, Fragai, Marco, Grifagni, Deborah, Barthel, Tatjana, Wollenhaupt, Jan, Weiss, Manfred S., Robertson, Angus, Bax, Adriaan, Sreeramulu, Sridhar, and Schwalbe, Harald

Abstract

The main protease Mpro, nsp5, of SARS-CoV-2 (SCoV2) is one of its most attractive drug targets. Here, we report primary screening data using nuclear magnetic resonance spectroscopy (NMR) of four different libraries and detailed follow-up synthesis on the promising uracil-containing fragment Z604 derived from these libraries. Z604 shows time-dependent binding. Its inhibitory effect is sensitive to reducing conditions. Starting with Z604, we synthesized and characterized 13 compounds designed by fragment growth strategies. Each compound was characterized by NMR and/or activity assays to investigate their interaction with Mpro. These investigations resulted in the four-armed compound 35b that binds directly to Mpro. 35b could be cocrystallized with Mpro revealing its noncovalent binding mode, which fills all four active site subpockets. Herein, we describe the NMR-derived fragment-to-hit pipeline and its application for the development of promising starting points for inhibitors of the main protease of SCoV2.

Published
2024
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4. Comprehensive Fragment Screening of the SARS‐CoV‐2 Proteome Explores Novel Chemical Space for Drug Development

Author

Berg, Hannes, Wirtz Martin, Maria A., Altincekic, Nadide, Alshamleh, Islam, Kaur Bains, Jasleen, Blechar, Julius, Ceylan, Betül, Jesus, Vanessa de, Dhamotharan, Karthikeyan, Fuks, Christin, Gande, Santosh L., Hargittay, Bruno, Hohmann, Katharina F., Hutchison, Marie T., Korn, Sophie Marianne, Krishnathas, Robin, Kutz, Felicitas, Linhard, Verena, Matzel, Tobias, Meiser, Nathalie, Niesteruk, Anna, Pyper, Dennis J., Schulte, Linda, Trucks, Sven, Azzaoui, Kamal, Blommers, Marcel J. J., Gadiya, Yojana, Karki, Reagon, Zaliani, Andrea, Gribbon, Philip, Silva Almeida, Marcius da, Dinis Anobom, Cristiane, Bula, Anna L., Bütikofer, Matthias, Putinhon Caruso, Ícaro, Caterina Felli, Isabella, Da Poian, Andrea T., Cardoso de Amorim, Gisele, Fourkiotis, Nikolaos K., Gallo, Angelo, Ghosh, Dhiman, Gomes‐Neto, Francisco, Gorbatyuk, Oksana, Hao, Bing, Kurauskas, Vilius, Lecoq, Lauriane, Li, Yunfeng, Cunha Mebus‐Antunes, Nathane, Mompeán, Miguel, Cristtina Neves‐Martins, Thais, Ninot‐Pedrosa, Martí, Pinheiro, Anderson S., Pontoriero, Letizia, Pustovalova, Yulia, Riek, Roland, Robertson, Angus J., Jose Abi Saad, Marie, Treviño, Miguel Á., Tsika, Aikaterini C., Almeida, Fabio C. L., Bax, Ad, Henzler‐Wildman, Katherine, Hoch, Jeffrey C., Jaudzems, Kristaps, Laurents, Douglas V., Orts, Julien, Pierattelli, Roberta, Spyroulias, Georgios A., Duchardt‐Ferner, Elke, Ferner, Jan, Fürtig, Boris, Hengesbach, Martin, Löhr, Frank, Qureshi, Nusrat, Richter, Christian, Saxena, Krishna, Schlundt, Andreas, Sreeramulu, Sridhar, Wacker, Anna, Weigand, Julia E., Wirmer‐Bartoschek, Julia, Wöhnert, Jens, Schwalbe, Harald, Berg, Hannes, Wirtz Martin, Maria A., Altincekic, Nadide, Alshamleh, Islam, Kaur Bains, Jasleen, Blechar, Julius, Ceylan, Betül, Jesus, Vanessa de, Dhamotharan, Karthikeyan, Fuks, Christin, Gande, Santosh L., Hargittay, Bruno, Hohmann, Katharina F., Hutchison, Marie T., Korn, Sophie Marianne, Krishnathas, Robin, Kutz, Felicitas, Linhard, Verena, Matzel, Tobias, Meiser, Nathalie, Niesteruk, Anna, Pyper, Dennis J., Schulte, Linda, Trucks, Sven, Azzaoui, Kamal, Blommers, Marcel J. J., Gadiya, Yojana, Karki, Reagon, Zaliani, Andrea, Gribbon, Philip, Silva Almeida, Marcius da, Dinis Anobom, Cristiane, Bula, Anna L., Bütikofer, Matthias, Putinhon Caruso, Ícaro, Caterina Felli, Isabella, Da Poian, Andrea T., Cardoso de Amorim, Gisele, Fourkiotis, Nikolaos K., Gallo, Angelo, Ghosh, Dhiman, Gomes‐Neto, Francisco, Gorbatyuk, Oksana, Hao, Bing, Kurauskas, Vilius, Lecoq, Lauriane, Li, Yunfeng, Cunha Mebus‐Antunes, Nathane, Mompeán, Miguel, Cristtina Neves‐Martins, Thais, Ninot‐Pedrosa, Martí, Pinheiro, Anderson S., Pontoriero, Letizia, Pustovalova, Yulia, Riek, Roland, Robertson, Angus J., Jose Abi Saad, Marie, Treviño, Miguel Á., Tsika, Aikaterini C., Almeida, Fabio C. L., Bax, Ad, Henzler‐Wildman, Katherine, Hoch, Jeffrey C., Jaudzems, Kristaps, Laurents, Douglas V., Orts, Julien, Pierattelli, Roberta, Spyroulias, Georgios A., Duchardt‐Ferner, Elke, Ferner, Jan, Fürtig, Boris, Hengesbach, Martin, Löhr, Frank, Qureshi, Nusrat, Richter, Christian, Saxena, Krishna, Schlundt, Andreas, Sreeramulu, Sridhar, Wacker, Anna, Weigand, Julia E., Wirmer‐Bartoschek, Julia, Wöhnert, Jens, and Schwalbe, Harald

Abstract

SARS‐CoV‐2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti‐virals. Within the international Covid19‐NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR‐detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure‐based drug design against the SCoV2 proteome.

Published
2024

6. Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies

Author

Altincekic, Nadide, primary, Jores, Nathalie, additional, Löhr, Frank, additional, Richter, Christian, additional, Ehrhardt, Claus, additional, Blommers, Marcel J. J., additional, Berg, Hannes, additional, Öztürk, Sare, additional, Gande, Santosh L., additional, Linhard, Verena, additional, Orts, Julien, additional, Abi Saad, Marie Jose, additional, Bütikofer, Matthias, additional, Kaderli, Janina, additional, Karlsson, B. Göran, additional, Brath, Ulrika, additional, Hedenström, Mattias, additional, Gröbner, Gerhard, additional, Sauer, Uwe H., additional, Perrakis, Anastassis, additional, Langer, Julian, additional, Banci, Lucia, additional, Cantini, Francesca, additional, Fragai, Marco, additional, Grifagni, Deborah, additional, Barthel, Tatjana, additional, Wollenhaupt, Jan, additional, Weiss, Manfred S., additional, Robertson, Angus, additional, Bax, Adriaan, additional, Sreeramulu, Sridhar, additional, and Schwalbe, Harald, additional

Published
2024
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9. A Polanyian Perspective on the Conflict Between Neoliberal Economics and Countrymindedness in Australian Drought and Water Policy.

Author

Robertson, Angus and Habib, Benjamin

Subjects
*DROUGHTS, *NEOLIBERALISM, *AGRICULTURAL policy, *GOVERNMENT policy, *ECONOMIC policy, *AGRICULTURE
Abstract

This article evaluates the successes and failures of Australian drought and water policy reforms. By analysing the influence of the ideas central to neoliberal economics and countrymindedness on the development and implementation of the National Drought Policy and the Murray Darling Basin Plan, we illustrate that drought and water policy reforms in Australia can be explained in the context of Karl Polanyi's double movement theory. We demonstrate that founding Australia's agricultural policy on economic assumptions is unlikely to be well‐received in a nation that exhibits widespread sympathy for the plight of agricultural producers. As such, we postulate that neoliberal agricultural policies that ignore the relevant social and historical context will be unpopular and vulnerable to a countermovement that undermines the intent and hinders the implementation of the policy. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Distinguishing Characteristics Between High and Low Adherence Patients Following Anterior Cruciate Ligament Reconstruction: A Qualitative Examination.

Author

Williams, Tom, Evans, Lynne, Robertson, Angus, Hardy, Lew, Roy, Stuart, and Lewis, Daniel

Subjects
ANTERIOR cruciate ligament surgery, PATIENT compliance, SPORTS psychology, SEMI-structured interviews
Abstract

The purpose of this study was to identify factors that distinguished between injured athletes who displayed high compared with low levels of rehabilitation adherence following anterior cruciate ligament reconstructive surgery. In order to gain an in-depth understanding of these factors, semistructured qualitative interviews were conducted with six high adherers, six matched low adherers and for each injured athlete, a significant other. Thematic analysis was used to identify the themes that distinguished between high and low adherers. Three themes were generated based on the findings: (a) preparation for postoperative rehabilitation, (b) an active versus passive approach to rehabilitation, and (c) the threat of a poor outcome. Each theme comprised a number of subthemes that further elucidated the participants' rehabilitation experiences and adherence behaviors. The findings have important implications for medical professionals, sport psychology consultants, coaches, and athletes with a vested interest in expediting recovery following anterior cruciate ligament reconstructive surgery. [ABSTRACT FROM AUTHOR]

Published
2022
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16. Comprehensive Fragment Screening of the SARS‐CoV‐2 Proteome Explores Novel Chemical Space for Drug Development

Author

Berg, Hannes, primary, Wirtz Martin, Maria A., additional, Altincekic, Nadide, additional, Alshamleh, Islam, additional, Kaur Bains, Jasleen, additional, Blechar, Julius, additional, Ceylan, Betül, additional, de Jesus, Vanessa, additional, Dhamotharan, Karthikeyan, additional, Fuks, Christin, additional, Gande, Santosh L., additional, Hargittay, Bruno, additional, Hohmann, Katharina F., additional, Hutchison, Marie T., additional, Marianne Korn, Sophie, additional, Krishnathas, Robin, additional, Kutz, Felicitas, additional, Linhard, Verena, additional, Matzel, Tobias, additional, Meiser, Nathalie, additional, Niesteruk, Anna, additional, Pyper, Dennis J., additional, Schulte, Linda, additional, Trucks, Sven, additional, Azzaoui, Kamal, additional, Blommers, Marcel J. J., additional, Gadiya, Yojana, additional, Karki, Reagon, additional, Zaliani, Andrea, additional, Gribbon, Philip, additional, da Silva Almeida, Marcius, additional, Dinis Anobom, Cristiane, additional, Bula, Anna L., additional, Bütikofer, Matthias, additional, Putinhon Caruso, Ícaro, additional, Caterina Felli, Isabella, additional, Da Poian, Andrea T., additional, Cardoso de Amorim, Gisele, additional, Fourkiotis, Nikolaos K., additional, Gallo, Angelo, additional, Ghosh, Dhiman, additional, Gomes‐Neto, Francisco, additional, Gorbatyuk, Oksana, additional, Hao, Bing, additional, Kurauskas, Vilius, additional, Lecoq, Lauriane, additional, Li, Yunfeng, additional, Cunha Mebus‐Antunes, Nathane, additional, Mompeán, Miguel, additional, Cristtina Neves‐Martins, Thais, additional, Ninot‐Pedrosa, Martí, additional, Pinheiro, Anderson S., additional, Pontoriero, Letizia, additional, Pustovalova, Yulia, additional, Riek, Roland, additional, Robertson, Angus J., additional, Jose Abi Saad, Marie, additional, Treviño, Miguel Á., additional, Tsika, Aikaterini C., additional, Almeida, Fabio C. L., additional, Bax, Ad, additional, Henzler‐Wildman, Katherine, additional, Hoch, Jeffrey C., additional, Jaudzems, Kristaps, additional, Laurents, Douglas V., additional, Orts, Julien, additional, Pierattelli, Roberta, additional, Spyroulias, Georgios A., additional, Duchardt‐Ferner, Elke, additional, Ferner, Jan, additional, Fürtig, Boris, additional, Hengesbach, Martin, additional, Löhr, Frank, additional, Qureshi, Nusrat, additional, Richter, Christian, additional, Saxena, Krishna, additional, Schlundt, Andreas, additional, Sreeramulu, Sridhar, additional, Wacker, Anna, additional, Weigand, Julia E., additional, Wirmer‐Bartoschek, Julia, additional, Wöhnert, Jens, additional, and Schwalbe, Harald, additional

Published
2022
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18. Large-Scale Recombinant Production of the SARS-CoV-2 Proteome for High-Throughput and Structural Biology Applications

Author

Altincekic, Nadide, Korn, Sophie Marianne, Qureshi, Nusrat Shahin, Dujardin, Marie, Ninot-Pedrosa, Martí, Abele, Rupert, Abi Saad, Marie Jose, Alfano, Caterina, Almeida, Fabio C. L., Alshamleh, Islam, de Amorim, Gisele Cardoso, Anderson, Thomas K., Anobom, Cristiane D., Anorma, Chelsea, Bains, Jasleen Kaur, Bax, Adriaan, Blackledge, Martin, Blechar, Julius, Böckmann, Anja, Brigandat, Louis, Bula, Anna, Bütikofer, Matthias, Camacho-Zarco, Aldo R., Carlomagno, Teresa, Caruso, Icaro Putinhon, Ceylan, Betül, Chaikuad, Apirat, Chu, Feixia, Cole, Laura, Crosby, Marquise G., Jesus, Vanessa de, Dhamotharan, Karthikeyan, Felli, Isabella C., Ferner, Jan, Fleischmann, Yanick, Fogeron, Marie-Laure, Fourkiotis, Nikolaos K., Fuks, Christin, Fürtig, Boris, Gallo, Angelo, Gande, Santosh L., Gerez, Juan Atilio, Ghosh, Dhiman, Gomes-Neto, Francisco, Gorbatyuk, Oksana, Guseva, Serafima, Hacker, Carolin, Häfner, Sabine, Hao, Bing, Hargittay, Bruno, Henzler-Wildman, K., Hoch, Jeffrey C., Hohmann, Katharina F., Hutchison, Marie T., Jaudzems, Kristaps, Jović, Katarina, Kaderli, Janina, Kalniņš, Gints, Kaņepe, Iveta, Kirchdoerfer, Robert N., Kirkpatrick, John, Knapp, Stefan, Krishnathas, Robin, Kutz, Felicitas, Lage, Susanne zur, Lambertz, Roderick, Lang, Andras, Laurents, Douglas, Lecoq, Lauriane, Linhard, Verena, Löhr, Frank, Malki, Anas, Bessa, Luiza Mamigonian, Martin, Rachel W., Matzel, Tobias, Maurin, Damien, McNutt, Seth W., Mebus-Antunes, Nathane Cunha, Meier, Beat H., Meiser, Nathalie, Mompeán, Miguel, Monaca, Elisa, Montserret, Roland, Mariño Perez, Laura, Moser, Celine, Muhle-Goll, Claudia, Neves-Martins, Thais Cristtina, Ni, Xiamonin, Norton-Baker, Brenna, Pierattelli, Roberta, Pontoriero, Letizia, Pustovalova, Yulia, Ohlenschläger, Oliver, Orts, Julien, Da Poian, Andrea T., Pyper, Dennis J., Richter, Christian, Riek, Roland, Rienstra, Chad M., Robertson, Angus, Pinheiro, Anderson S., Sabbatella, Raffaele, Salvi, Nicola, Saxena, Krishna, Schulte, Linda, Schiavina, Marco, Schwalbe, Harald, Silber, Mara, da Silva Almeida, Marcius, Sprague-Piercy, Marc A., Spyroulias, Georgios A., Sreeramulu, Sridhar, Tants, Jan-Niklas, Tārs, Kaspars, Torres, Felix, Töws, Sabrina, Treviño, Miguel Á., Trucks, Sven, Tsika, Aikaterini C., Varga, Krisztina, Wang, Ying, Weber, Marco E., Weigand, Julia E., Wiedemann, Christoph, Wirmer-Bartoschek, Julia, Wirtz Martin, Maria Alexandra, Zehnder, Johannes, Hengesbach, Martin, Schlundt, Andreas, Altincekic, Nadide, Korn, Sophie Marianne, Qureshi, Nusrat Shahin, Dujardin, Marie, Ninot-Pedrosa, Martí, Abele, Rupert, Abi Saad, Marie Jose, Alfano, Caterina, Almeida, Fabio C. L., Alshamleh, Islam, de Amorim, Gisele Cardoso, Anderson, Thomas K., Anobom, Cristiane D., Anorma, Chelsea, Bains, Jasleen Kaur, Bax, Adriaan, Blackledge, Martin, Blechar, Julius, Böckmann, Anja, Brigandat, Louis, Bula, Anna, Bütikofer, Matthias, Camacho-Zarco, Aldo R., Carlomagno, Teresa, Caruso, Icaro Putinhon, Ceylan, Betül, Chaikuad, Apirat, Chu, Feixia, Cole, Laura, Crosby, Marquise G., Jesus, Vanessa de, Dhamotharan, Karthikeyan, Felli, Isabella C., Ferner, Jan, Fleischmann, Yanick, Fogeron, Marie-Laure, Fourkiotis, Nikolaos K., Fuks, Christin, Fürtig, Boris, Gallo, Angelo, Gande, Santosh L., Gerez, Juan Atilio, Ghosh, Dhiman, Gomes-Neto, Francisco, Gorbatyuk, Oksana, Guseva, Serafima, Hacker, Carolin, Häfner, Sabine, Hao, Bing, Hargittay, Bruno, Henzler-Wildman, K., Hoch, Jeffrey C., Hohmann, Katharina F., Hutchison, Marie T., Jaudzems, Kristaps, Jović, Katarina, Kaderli, Janina, Kalniņš, Gints, Kaņepe, Iveta, Kirchdoerfer, Robert N., Kirkpatrick, John, Knapp, Stefan, Krishnathas, Robin, Kutz, Felicitas, Lage, Susanne zur, Lambertz, Roderick, Lang, Andras, Laurents, Douglas, Lecoq, Lauriane, Linhard, Verena, Löhr, Frank, Malki, Anas, Bessa, Luiza Mamigonian, Martin, Rachel W., Matzel, Tobias, Maurin, Damien, McNutt, Seth W., Mebus-Antunes, Nathane Cunha, Meier, Beat H., Meiser, Nathalie, Mompeán, Miguel, Monaca, Elisa, Montserret, Roland, Mariño Perez, Laura, Moser, Celine, Muhle-Goll, Claudia, Neves-Martins, Thais Cristtina, Ni, Xiamonin, Norton-Baker, Brenna, Pierattelli, Roberta, Pontoriero, Letizia, Pustovalova, Yulia, Ohlenschläger, Oliver, Orts, Julien, Da Poian, Andrea T., Pyper, Dennis J., Richter, Christian, Riek, Roland, Rienstra, Chad M., Robertson, Angus, Pinheiro, Anderson S., Sabbatella, Raffaele, Salvi, Nicola, Saxena, Krishna, Schulte, Linda, Schiavina, Marco, Schwalbe, Harald, Silber, Mara, da Silva Almeida, Marcius, Sprague-Piercy, Marc A., Spyroulias, Georgios A., Sreeramulu, Sridhar, Tants, Jan-Niklas, Tārs, Kaspars, Torres, Felix, Töws, Sabrina, Treviño, Miguel Á., Trucks, Sven, Tsika, Aikaterini C., Varga, Krisztina, Wang, Ying, Weber, Marco E., Weigand, Julia E., Wiedemann, Christoph, Wirmer-Bartoschek, Julia, Wirtz Martin, Maria Alexandra, Zehnder, Johannes, Hengesbach, Martin, and Schlundt, Andreas

Abstract

The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.

Published
2022

19. Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development

Author

State of Hesse, German Research Foundation, European Commission, Ministero dell'Istruzione, dell'Università e della Ricerca, Agence Nationale de la Recherche (France), Centre National de la Recherche Scientifique (France), National Institutes of Health (US), National Science Foundation (US), Latvian Council of Science, Berg, Hannes [0000-0002-2060-4296], Wirtz Martin, Maria A. [0000-0002-0318-7785], Altincekic, Nadide [0000-0001-6370-3414], Alshamleh, Islam [0000-0001-6714-3602], Dhamotharan, Karthikeyan [0000-0003-0226-7350], Marianne Korn, Sophie [0000-0003-3798-3277], Schulte, Linda [0000-0002-9334-8908], da Silva Almeida, Marcius [0000-0003-4921-8185], Caterina Felli, Isabella [0000-0002-6018-9090], Fourkiotis, Nikolaos K. [0000-0002-5197-4142], Gallo, Angelo [0000-0001-9778-4822], Ninot-Pedrosa, Martí [0000-0003-2851-9990], Pontoriero, Letizia [0000-0002-5586-1305], Treviño, Miguel A. [0000-0002-0738-5973], Tsika, Aikaterini C. [000-0002-3723-0606], Almeida, Fabio C.L. [0000-0001-6046-7006], Bax, Ad [0000-0002-9809-5700], Henzler-Wildman, Katherine [0000-0002-5295-2121], Hoch, Jeffrey C. [0000-0002-9230-2019], Jaudzems, Kristaps [0000-0003-3922-2447], Laurents, D.V. [0000-0002-4187-165X], Ferner, Jan [0000-0002-2009-3203], Hengesbach, Martin [0000-0001-9414-1602], Löhr, Frank [0000-0001-6399-9497], Qureshi, Nusrat [0000-0002-5753-5984], Richter, Christian [0000-0002-5420-2826], Schlundt, Andreas [0000-0003-2254-7560], Weigand, Julia E. [0000-0003-4247-1348], Wirmer-Bartoschek, Julia [0000-0002-0642-1311], Schwalbe, Harald [0000-0001-5693-7909], Berg, Hannes, Wirtz Martin, Maria A., Altincekic, Nadide, Alshamleh, Islam, Kaur Bains, Jasleen, Blechar, Julius, Ceylan, Betül, Jesus, Vanessa de, Dhamotharan, Karthikeyan, Fuks, Christin, Gande, Santosh L., Hargittay, Bruno, Hohmann, Katharina F., Hutchison, Marie T., Marianne Korn, Sophie, Krishnathas, Robin, Kutz, Felicitas, Linhard, Verena, Matzel, Tobias, Meiser, Nathalie, Niesteruk, Anna, Pyper, Dennis J., Schulte, Linda, Trucks, Sven, Azzaoui, Kamal, Blommers, Marcel J.J., Gadiya, Yojana, Karki, Reagon, Zaliani, Andrea, Gribbon, Philip, da Silva Almeida, Marcius, Dinis Anobom, Cristiane, Bula, Anna L., Bütikofer, Matthias, Putinhon Caruso, Ícaro, Caterina Felli, Isabella, Da Poian, Andrea T., Cardoso de Amorim, Gisele, Fourkiotis, Nikolaos K., Gallo, Angelo, Ghosh, Dhiman, Gomes-Neto, Francisco, Gorbatyuk, Oksana, Hao, Bing, Kurauskas, Vilius, Lecoq, Lauriane, Li, Yunfeng, Cunha Mebus-Antunes, Nathane, Mompeán, Miguel, Cristtina Neves-Martins, Thais, Ninot-Pedrosa, Martí, Pinheiro, Anderson S.., Pontoriero, Letizia, Pustovalova, Yulia, Riek, Roland, Robertson, Angus J., Jose Abi Saad, Marie, Treviño, Miguel A., Tsika, Aikaterini C., Almeida, Fabio C.L., Bax, Ad, Henzler-Wildman, Katherine, Hoch, Jeffrey C., Jaudzems, Kristaps, Laurents, Douglas V., Orts, Julien, Pierattelli, Roberta, Spyroulias, Georgios A., Duchardt-Ferner, Elke, Ferner, Jan, Fürtig, Boris, Hengesbach, Martin, Löhr, Frank, Qureshi, Nusrat, Richter, Christian, Saxena, Krishna, Schlundt, Andreas, Sreeramulu, Sridhar, Wacker, Anna, Weigand, Julia E., Wirmer-Bartoschek, Julia, Wöhnert, Jens, Schwalbe, Harald, State of Hesse, German Research Foundation, European Commission, Ministero dell'Istruzione, dell'Università e della Ricerca, Agence Nationale de la Recherche (France), Centre National de la Recherche Scientifique (France), National Institutes of Health (US), National Science Foundation (US), Latvian Council of Science, Berg, Hannes [0000-0002-2060-4296], Wirtz Martin, Maria A. [0000-0002-0318-7785], Altincekic, Nadide [0000-0001-6370-3414], Alshamleh, Islam [0000-0001-6714-3602], Dhamotharan, Karthikeyan [0000-0003-0226-7350], Marianne Korn, Sophie [0000-0003-3798-3277], Schulte, Linda [0000-0002-9334-8908], da Silva Almeida, Marcius [0000-0003-4921-8185], Caterina Felli, Isabella [0000-0002-6018-9090], Fourkiotis, Nikolaos K. [0000-0002-5197-4142], Gallo, Angelo [0000-0001-9778-4822], Ninot-Pedrosa, Martí [0000-0003-2851-9990], Pontoriero, Letizia [0000-0002-5586-1305], Treviño, Miguel A. [0000-0002-0738-5973], Tsika, Aikaterini C. [000-0002-3723-0606], Almeida, Fabio C.L. [0000-0001-6046-7006], Bax, Ad [0000-0002-9809-5700], Henzler-Wildman, Katherine [0000-0002-5295-2121], Hoch, Jeffrey C. [0000-0002-9230-2019], Jaudzems, Kristaps [0000-0003-3922-2447], Laurents, D.V. [0000-0002-4187-165X], Ferner, Jan [0000-0002-2009-3203], Hengesbach, Martin [0000-0001-9414-1602], Löhr, Frank [0000-0001-6399-9497], Qureshi, Nusrat [0000-0002-5753-5984], Richter, Christian [0000-0002-5420-2826], Schlundt, Andreas [0000-0003-2254-7560], Weigand, Julia E. [0000-0003-4247-1348], Wirmer-Bartoschek, Julia [0000-0002-0642-1311], Schwalbe, Harald [0000-0001-5693-7909], Berg, Hannes, Wirtz Martin, Maria A., Altincekic, Nadide, Alshamleh, Islam, Kaur Bains, Jasleen, Blechar, Julius, Ceylan, Betül, Jesus, Vanessa de, Dhamotharan, Karthikeyan, Fuks, Christin, Gande, Santosh L., Hargittay, Bruno, Hohmann, Katharina F., Hutchison, Marie T., Marianne Korn, Sophie, Krishnathas, Robin, Kutz, Felicitas, Linhard, Verena, Matzel, Tobias, Meiser, Nathalie, Niesteruk, Anna, Pyper, Dennis J., Schulte, Linda, Trucks, Sven, Azzaoui, Kamal, Blommers, Marcel J.J., Gadiya, Yojana, Karki, Reagon, Zaliani, Andrea, Gribbon, Philip, da Silva Almeida, Marcius, Dinis Anobom, Cristiane, Bula, Anna L., Bütikofer, Matthias, Putinhon Caruso, Ícaro, Caterina Felli, Isabella, Da Poian, Andrea T., Cardoso de Amorim, Gisele, Fourkiotis, Nikolaos K., Gallo, Angelo, Ghosh, Dhiman, Gomes-Neto, Francisco, Gorbatyuk, Oksana, Hao, Bing, Kurauskas, Vilius, Lecoq, Lauriane, Li, Yunfeng, Cunha Mebus-Antunes, Nathane, Mompeán, Miguel, Cristtina Neves-Martins, Thais, Ninot-Pedrosa, Martí, Pinheiro, Anderson S.., Pontoriero, Letizia, Pustovalova, Yulia, Riek, Roland, Robertson, Angus J., Jose Abi Saad, Marie, Treviño, Miguel A., Tsika, Aikaterini C., Almeida, Fabio C.L., Bax, Ad, Henzler-Wildman, Katherine, Hoch, Jeffrey C., Jaudzems, Kristaps, Laurents, Douglas V., Orts, Julien, Pierattelli, Roberta, Spyroulias, Georgios A., Duchardt-Ferner, Elke, Ferner, Jan, Fürtig, Boris, Hengesbach, Martin, Löhr, Frank, Qureshi, Nusrat, Richter, Christian, Saxena, Krishna, Schlundt, Andreas, Sreeramulu, Sridhar, Wacker, Anna, Weigand, Julia E., Wirmer-Bartoschek, Julia, Wöhnert, Jens, and Schwalbe, Harald

Abstract

SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome.

Published
2022

20. Glenohumeral Migration of Intraosseous Suture- Button after Acromioclavicular JointACJ Reconstruction – A Case Report

Author

Panesar, Karan Singh and Robertson, Angus

Subjects
Glenohumeral joint, Acromioclavicular joint ACJ separation, Case Report, Suture-button migration
Abstract

Introduction: Acromioclavicular joint (ACJ) separation is a common sports injury. Suture- button repair is favoured technique with a complication rate of 20%. We are the first to report the migration of a suture button into the glenohumeral joint. Case Report: A 28-year-old right-handed rugby player presented with symptoms of laxity and catching within the right shoulder 4 years after reconstruction using an ACJ Dog Bone TM Technique (Arthrex Inc.). Magnetic resonance imaging showed that the coracoid suture button had migrated into the glenohumeral joint. Conclusion: The patient was successfully treated with an arthroscopic examination of the glenohumeral joint and removal of the button. We outline the risk factors and treatment options involved in this unique presentation.

Published
2020

22. An Enzyme with High Catalytic Proficiency Utilizes Distal Site Substrate Binding Energy to Stabilize the Closed State but at the Expense of Substrate Inhibition

Author

Robertson, Angus J., primary, Cruz-Navarrete, F. Aaron, additional, Wood, Henry P., additional, Vekaria, Nikita, additional, Hounslow, Andrea M., additional, Bisson, Claudine, additional, Cliff, Matthew J., additional, Baxter, Nicola J., additional, and Waltho, Jonathan P., additional

Published
2022
Full Text
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27. Large-Scale Recombinant Production of the SARS-CoV-2 Proteome for High-Throughput and Structural Biology Applications

Author

Altincekic, Nadide, Korn, Sophie Marianne, Qureshi, Nusrat Shahin, Dujardin, Marie, Ninot-Pedrosa, Martí, Abele, Rupert, Abi Saad, Marie Jose, Alfano, Caterina, Almeida, Fabio, Alshamleh, Islam, de Amorim, Gisele Cardoso, Anderson, Thomas, Anobom, Cristiane, Anorma, Chelsea, Bains, Jasleen Kaur, Bax, Adriaan, Blackledge, Martin, Blechar, Julius, Böckmann, Anja, Brigandat, Louis, Bula, Anna, Bütikofer, Matthias, Camacho-Zarco, Aldo, Carlomagno, Teresa, Caruso, Icaro Putinhon, Ceylan, Betül, Chaikuad, Apirat, Chu, Feixia, Cole, Laura, Crosby, Marquise, de Jesus, Vanessa, Dhamotharan, Karthikeyan, Felli, Isabella, Ferner, Jan, Fleischmann, Yanick, Fogeron, Marie-Laure, Fourkiotis, Nikolaos, Fuks, Christin, Fürtig, Boris, Gallo, Angelo, Gande, Santosh, Gerez, Juan Atilio, Ghosh, Dhiman, GOMES-NETO, Francisco, Gorbatyuk, Oksana, Guseva, Serafima, Hacker, Carolin, Häfner, Sabine, Hao, Bing, Hargittay, Bruno, Henzler-Wildman, K., Hoch, Jeffrey, Hohmann, Katharina, Hutchison, Marie, Jaudzems, Kristaps, Jović, Katarina, Kaderli, Janina, Kalniņš, Gints, Kaņepe, Iveta, Kirchdoerfer, Robert, Kirkpatrick, John, Knapp, Stefan, Krishnathas, Robin, Kutz, Felicitas, zur Lage, Susanne, Lambertz, Roderick, Lang, Andras, Laurents, Douglas, Lecoq, Lauriane, Linhard, Verena, Löhr, Frank, Malki, Anas, Bessa, Luiza Mamigonian, Martin, Rachel, Matzel, Tobias, Maurin, Damien, McNutt, Seth, Mebus-Antunes, Nathane Cunha, Meier, Beat, Meiser, Nathalie, Mompeán, Miguel, Monaca, Elisa, Montserret, Roland, Mariño Perez, Laura, Moser, Celine, Muhle-Goll, Claudia, Neves-Martins, Thais Cristtina, Ni, Xiamonin, Norton-Baker, Brenna, Pierattelli, Roberta, Pontoriero, Letizia, Pustovalova, Yulia, Ohlenschläger, Oliver, Orts, Julien, Da Poian, Andrea, Pyper, Dennis, Richter, Christian, Riek, Roland, Rienstra, Chad, Robertson, Angus, Pinheiro, Anderson, Sabbatella, Raffaele, Salvi, Nicola, Saxena, Krishna, Schulte, Linda, Schiavina, Marco, Schwalbe, Harald, Silber, Mara, Almeida, Marcius da Silva, Sprague-Piercy, Marc, Spyroulias, Georgios, Sreeramulu, Sridhar, Tants, Jan-Niklas, Tārs, Kaspars, Torres, Felix, Töws, Sabrina, Treviño, Miguel, Trucks, Sven, Tsika, Aikaterini, Varga, Krisztina, Wang, Ying, Weber, Marco, Weigand, Julia, Wiedemann, Christoph, Wirmer-Bartoschek, Julia, Wirtz Martin, Maria Alexandra, Zehnder, Johannes, Hengesbach, Martin, Schlundt, Andreas, Treviño, Miguel Á., Institute of Biophysical Chemistry, Center for Biomolecular Magnetic Resonance (BMRZ), Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), Goethe University Frankfurt am Main, German Research Foundation, Cassa di Risparmio di Firenze, European Commission, University of New Hampshire, The Free State of Thuringia, National Institutes of Health (US), National Science Foundation (US), Howard Hughes Medical Institute, Latvian Council of Science, Ministry of Development and Investments (Greece), Helmholtz Association, Centre National de la Recherche Scientifique (France), Agence Nationale de la Recherche (France), Fondation pour la Recherche Médicale, Swiss National Science Foundation, Fonds National Suisse de la Recherche Scientifique, ETH Zurich, European Research Council, Université Grenoble Alpes, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación 'la Caixa', Instituto de Salud Carlos III, Boehringer Ingelheim Fonds, Ministero dell'Istruzione, dell'Università e della Ricerca, Polytechnic Foundation of Frankfurt am Main, Goethe University Frankfurt, CNRS/Lyon University, Fondazione Ri.MED, Federal University of Rio de Janeiro, Caxias Federal University of Rio de Janeiro, University of Wisconsin-Madison, University of California, NIDDK, IBS, Latvian Institute of Organic Synthesis, Leibniz University Hannover, Helmholtz Centre for Infection Research, Universidade Estadual Paulista (Unesp), Buchmann Institute for Molecular Life Sciences, University of Florence, University of Patras, Oswaldo Cruz Foundation (FIOCRUZ), UConn Health, Signals GmbH Co. KG, Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), Latvian Biomedical Research and Study Centre, Spanish National Research Council (CSIC), Karlsruhe Institute of Technology, Technical University of Darmstadt, Martin Luther University Halle-Wittenberg, Altincekic N., Korn S.M., Qureshi N.S., Dujardin M., Ninot-Pedrosa M., Abele R., Abi Saad M.J., Alfano C., Almeida F.C.L., Alshamleh I., de Amorim G.C., Anderson T.K., Anobom C.D., Anorma C., Bains J.K., Bax A., Blackledge M., Blechar J., Bockmann A., Brigandat L., Bula A., Butikofer M., Camacho-Zarco A.R., Carlomagno T., Caruso I.P., Ceylan B., Chaikuad A., Chu F., Cole L., Crosby M.G., de Jesus V., Dhamotharan K., Felli I.C., Ferner J., Fleischmann Y., Fogeron M.-L., Fourkiotis N.K., Fuks C., Furtig B., Gallo A., Gande S.L., Gerez J.A., Ghosh D., Gomes-Neto F., Gorbatyuk O., Guseva S., Hacker C., Hafner S., Hao B., Hargittay B., Henzler-Wildman K., Hoch J.C., Hohmann K.F., Hutchison M.T., Jaudzems K., Jovic K., Kaderli J., Kalnins G., Kanepe I., Kirchdoerfer R.N., Kirkpatrick J., Knapp S., Krishnathas R., Kutz F., zur Lage S., Lambertz R., Lang A., Laurents D., Lecoq L., Linhard V., Lohr F., Malki A., Bessa L.M., Martin R.W., Matzel T., Maurin D., McNutt S.W., Mebus-Antunes N.C., Meier B.H., Meiser N., Mompean M., Monaca E., Montserret R., Marino Perez L., Moser C., Muhle-Goll C., Neves-Martins T.C., Ni X., Norton-Baker B., Pierattelli R., Pontoriero L., Pustovalova Y., Ohlenschlager O., Orts J., Da Poian A.T., Pyper D.J., Richter C., Riek R., Rienstra C.M., Robertson A., Pinheiro A.S., Sabbatella R., Salvi N., Saxena K., Schulte L., Schiavina M., Schwalbe H., Silber M., Almeida M.D.S., Sprague-Piercy M.A., Spyroulias G.A., Sreeramulu S., Tants J.-N., Tars K., Torres F., Tows S., Trevino M.A., Trucks S., Tsika A.C., Varga K., Wang Y., Weber M.E., Weigand J.E., Wiedemann C., Wirmer-Bartoschek J., Wirtz Martin M.A., Zehnder J., Hengesbach M., Schlundt A., HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., and Obra Social la Caixa

Subjects
Life sciences, biology, SARS-COV-2, COVID-19, protein production, structural biology, NMR, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Biochemistry, Genetics and Molecular Biology (miscellaneous), Biochemistry, Accessory proteins, NMR spectroscopy, ddc:570, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Biosciences, ddc:610, Nonstructural proteins, Molecular Biology, Original Research, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], SARS-CoV-2, Intrinsically disordered region, nonstructural proteins, structural proteins, Cell-free protein synthesis, intrinsically disordered region, cell-free protein synthesis, accessory proteins, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Structural proteins
Abstract

The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form., This work was supported by Goethe University (Corona funds), the DFG-funded CRC: “Molecular Principles of RNA-Based Regulation,” DFG infrastructure funds (project numbers: 277478796, 277479031, 392682309, 452632086, 70653611), the state of Hesse (BMRZ), the Fondazione CR Firenze (CERM), and the IWB-EFRE-program 20007375. This project has received funding from the European Union’s Horizon 2020 research and innovation program under Grant Agreement No. 871037. AS is supported by DFG Grant SCHL 2062/2-1 and by the JQYA at Goethe through project number 2019/AS01. Work in the lab of KV was supported by a CoRE grant from the University of New Hampshire. The FLI is a member of the Leibniz Association (WGL) and financially supported by the Federal Government of Germany and the State of Thuringia. Work in the lab of RM was supported by NIH (2R01EY021514) and NSF (DMR-2002837). BN-B was supported by theNSF GRFP.MCwas supported byNIH (R25 GM055246 MBRS IMSD), and MS-P was supported by the HHMI Gilliam Fellowship. Work in the labs of KJ and KT was supported by Latvian Council of Science Grant No. VPP-COVID 2020/1-0014. Work in the UPAT’s lab was supported by the INSPIRED (MIS 5002550) project, which is implemented under the Action “Reinforcement of the Research and Innovation Infrastructure,” funded by the Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and cofinanced by Greece and the EU (European Regional Development Fund) and the FP7 REGPOT CT-2011- 285950–“SEE-DRUG” project (purchase of UPAT’s 700MHz NMR equipment). Work in the CM-G lab was supported by the Helmholtz society. Work in the lab of ABö was supported by the CNRS, the French National Research Agency (ANR, NMRSCoV2- ORF8), the Fondation de la Recherche Médicale (FRM, NMR-SCoV2-ORF8), and the IR-RMN-THC Fr3050 CNRS. Work in the lab of BM was supported by the Swiss National Science Foundation (Grant number 200020_188711), the Günthard Stiftung für Physikalische Chemie, and the ETH Zurich. Work in the labs of ABö and BM was supported by a common grant from SNF (grant 31CA30_196256). This work was supported by the ETHZurich, the grant ETH40 18 1, and the grant Krebsliga KFS 4903 08 2019. Work in the lab of the IBS Grenoble was supported by the Agence Nationale de Recherche (France) RA-COVID SARS2NUCLEOPROTEIN and European Research Council Advanced Grant DynamicAssemblies. Work in the CA lab was supported by Patto per il Sud della Regione Siciliana–CheMISt grant (CUP G77B17000110001). Part of this work used the platforms of the Grenoble Instruct-ERIC center (ISBG; UMS 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology (PSB), supported by FRISBI (ANR-10-INBS-05-02) and GRAL, financed within the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE- 0003). Work at the UW-Madison was supported by grant numbers NSF MCB2031269 and NIH/NIAID AI123498. MM is a Ramón y Cajal Fellow of the Spanish AEI-Ministry of Science and Innovation (RYC2019-026574-I), and a “La Caixa” Foundation (ID 100010434) Junior Leader Fellow (LCR/BQ/PR19/11700003). Funded by project COV20/00764 fromthe Carlos III Institute of Health and the SpanishMinistry of Science and Innovation to MMand DVL. VDJ was supported by the Boehringer Ingelheim Fonds. Part of this work used the resources of the Italian Center of Instruct-ERIC at the CERM/ CIRMMP infrastructure, supported by the Italian Ministry for University and Research (FOE funding). CF was supported by the Stiftung Polytechnische Gesellschaft. Work in the lab of JH was supported by NSF (RAPID 2030601) and NIH (R01GM123249).

Published
2021
Full Text
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28. Large-Scale Recombinant Production of the SARS-CoV-2 Proteome for High-Throughput and Structural Biology Applications

Author

Altınçekiç, Nadide, Korn, Sophie Marianne, Qureshi, Nusrat Shahin, Dujardin, Marie, Ninot-Pedrosa, Martí, Abele, Rupert, Abi Saad, Marie Jose, Alfano, Caterina, Almeida, Fabio C. L., Alshamleh, Islam, Amorim, Gisele Cardoso de, Anderson, Thomas K., Anobom, Cristiane D., Anorma, Chelsea, Bains, Jasleen Kaur, Bax, Adriaan, Blackledge, Martin, Blechar, Julius, Böckmann, Anja, Brigandat, Louis, Bula, Anna, Bütikofer, Matthias, Camacho-Zarco, Aldo R., Carlomagno, Teresa, Caruso, Icaro Putinhon, Ceylan, Betül, Chaikuad, Apirat, Chu, Feixia, Cole, Laura, Crosby, Marquise G., De Jesus, Vanessa, Dhamotharan, Karthikeyan, Felli, Isabella C., Ferner, Jan, Fleischmann, Yanick, Fogeron, Marie-Laure, Fourkiotis, Nikolaos K., Fuks, Christin, Fürtig, Boris, Gallo, Angelo, Gande, Santosh L., Gerez, Juan Atilio, Ghosh, Dhiman, Gomes-Neto, Francisco, Gorbatyuk, Oksana, Guseva, Serafima, Hacker, Carolin, Häfner, Sabine, Hao, Bing, Hargittay, Bruno, Henzler-Wildman, Katherine, Hoch, Jeffrey C., Hohmann, Katharina Felicitas, Hutchison, Marie T., Jaudzems, Kristaps, Jović, Katarina, Kaderli, Janina, Kalnins, Gints, Kanepe, Iveta, Kirchdoerfer, Robert N., Kirkpatrick, John, Knapp, Stefan, Krishnathas, Robin, Kutz, Felicitas, Zur Lage, Susanne, Lambertz, Roderick, Lang, Andras, Laurents, Douglas, Lecoq, Lauriane, Linhard, Verena, Löhr, Frank, Malki, Anas, Bessa, Luiza Mamigonian, Martin, Rachel W., Matzel, Tobias, Maurin, Damien, McNutt, Seth W., Mebus-Antunes, Nathane Cunha, Meier, Beat H., Meiser, Nathalie, Mompeán, Miguel, Monaca, Elisa, Montserret, Roland, Perez, Laura Mariño, Moser, Celine, Muhle-Goll, Claudia, Neves-Martins, Thais Cristtina, Ni, Xiamonin, Norton-Baker, Brenna, Pierattelli, Roberta, Pontoriero, Letizia, Pustovalova, Yulia, Ohlenschläger, Oliver, Orts, Julien, Poian, Andrea T. da, Pyper, Dennis Joshua, Richter, Christian, Riek, Roland, Rienstra, Chad M., Robertson, Angus, Pinheiro, Anderson S., Sabbatella, Raffaele, Salvi, Nicola, Saxena, Krishna, Schulte, Linda, Schiavina, Marco, Schwalbe, Harald, Silber, Mara, Almeida, Marcius da Silva, Sprague-Piercy, Marc A., Spyroulias, Georgios A., Sreeramulu, Sridhar, Tants, Jan-Niklas, Tars, Kaspars, Torres, Felix, Töws, Sabrina, Trevino, Miguel A., Trucks, Sven, Tsika, Aikaterini C., Varga, Krisztina, Wang, Ying, Weber, Marco E., Weigand, Julia E., Wiedemann, Christoph, Wirmer-Bartoschek, Julia, Wirtz Martin, Maria Alexandra, Zehnder, Johannes, Hengesbach, Martin, Schlundt, Andreas, Altınçekiç, Nadide, Korn, Sophie Marianne, Qureshi, Nusrat Shahin, Dujardin, Marie, Ninot-Pedrosa, Martí, Abele, Rupert, Abi Saad, Marie Jose, Alfano, Caterina, Almeida, Fabio C. L., Alshamleh, Islam, Amorim, Gisele Cardoso de, Anderson, Thomas K., Anobom, Cristiane D., Anorma, Chelsea, Bains, Jasleen Kaur, Bax, Adriaan, Blackledge, Martin, Blechar, Julius, Böckmann, Anja, Brigandat, Louis, Bula, Anna, Bütikofer, Matthias, Camacho-Zarco, Aldo R., Carlomagno, Teresa, Caruso, Icaro Putinhon, Ceylan, Betül, Chaikuad, Apirat, Chu, Feixia, Cole, Laura, Crosby, Marquise G., De Jesus, Vanessa, Dhamotharan, Karthikeyan, Felli, Isabella C., Ferner, Jan, Fleischmann, Yanick, Fogeron, Marie-Laure, Fourkiotis, Nikolaos K., Fuks, Christin, Fürtig, Boris, Gallo, Angelo, Gande, Santosh L., Gerez, Juan Atilio, Ghosh, Dhiman, Gomes-Neto, Francisco, Gorbatyuk, Oksana, Guseva, Serafima, Hacker, Carolin, Häfner, Sabine, Hao, Bing, Hargittay, Bruno, Henzler-Wildman, Katherine, Hoch, Jeffrey C., Hohmann, Katharina Felicitas, Hutchison, Marie T., Jaudzems, Kristaps, Jović, Katarina, Kaderli, Janina, Kalnins, Gints, Kanepe, Iveta, Kirchdoerfer, Robert N., Kirkpatrick, John, Knapp, Stefan, Krishnathas, Robin, Kutz, Felicitas, Zur Lage, Susanne, Lambertz, Roderick, Lang, Andras, Laurents, Douglas, Lecoq, Lauriane, Linhard, Verena, Löhr, Frank, Malki, Anas, Bessa, Luiza Mamigonian, Martin, Rachel W., Matzel, Tobias, Maurin, Damien, McNutt, Seth W., Mebus-Antunes, Nathane Cunha, Meier, Beat H., Meiser, Nathalie, Mompeán, Miguel, Monaca, Elisa, Montserret, Roland, Perez, Laura Mariño, Moser, Celine, Muhle-Goll, Claudia, Neves-Martins, Thais Cristtina, Ni, Xiamonin, Norton-Baker, Brenna, Pierattelli, Roberta, Pontoriero, Letizia, Pustovalova, Yulia, Ohlenschläger, Oliver, Orts, Julien, Poian, Andrea T. da, Pyper, Dennis Joshua, Richter, Christian, Riek, Roland, Rienstra, Chad M., Robertson, Angus, Pinheiro, Anderson S., Sabbatella, Raffaele, Salvi, Nicola, Saxena, Krishna, Schulte, Linda, Schiavina, Marco, Schwalbe, Harald, Silber, Mara, Almeida, Marcius da Silva, Sprague-Piercy, Marc A., Spyroulias, Georgios A., Sreeramulu, Sridhar, Tants, Jan-Niklas, Tars, Kaspars, Torres, Felix, Töws, Sabrina, Trevino, Miguel A., Trucks, Sven, Tsika, Aikaterini C., Varga, Krisztina, Wang, Ying, Weber, Marco E., Weigand, Julia E., Wiedemann, Christoph, Wirmer-Bartoschek, Julia, Wirtz Martin, Maria Alexandra, Zehnder, Johannes, Hengesbach, Martin, and Schlundt, Andreas

Abstract

The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.

Published
2021

29. Large-Scale Recombinant Production of the SARS-CoV-2 Proteome for High-Throughput and Structural Biology Applications

Author

Goethe University Frankfurt am Main, German Research Foundation, Cassa di Risparmio di Firenze, European Commission, University of New Hampshire, The Free State of Thuringia, National Institutes of Health (US), National Science Foundation (US), Howard Hughes Medical Institute, Latvian Council of Science, Ministry of Development and Investments (Greece), Helmholtz Association, Centre National de la Recherche Scientifique (France), Agence Nationale de la Recherche (France), Fondation pour la Recherche Médicale, Swiss National Science Foundation, Fonds National Suisse de la Recherche Scientifique, ETH Zurich, European Research Council, Université Grenoble Alpes, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación la Caixa, Instituto de Salud Carlos III, Boehringer Ingelheim Fonds, Ministero dell'Istruzione, dell'Università e della Ricerca, Polytechnic Foundation of Frankfurt am Main, Altincekic, Nadide, Korn, Sophie Marianne, Qureshi, Nusrat Shahin, Dujardin, Marie, Ninot-Pedrosa, Martí, Abele, Rupert, Abi Saad, Marie Jose, Alfano, Caterina, Almeida, Fabio C. L., Alshamleh, Islam, Cardoso de Amorim, Gisele, Anorma, Chelsea, Bains, Jasleen Kaur, Bax, Andriaan, Blackledge, Martin, Blechar, Julius, Böckmann, Anja, Brigandat, Louis, Bula, Anna, Bütikofer, Matthias, Camacho-Zarco, Aldo R., Ghosh, Dhiman, Carlomagno, Teresa, Caruso, Icaro Putinhon, Ceylan, Betül, Chaikuad, Apirat, Chu, Feixia, Cole, Laura, Crosby, Marquise G., Jesus, Vanessa de, Dhamotharan, Karthikeyan, Felli, Isabella C., Gomes-Neto, Francisco, Ferner, Jan, Fleischmann, Yanick, Fogeron, Marie-Laure, Fourkiotis, Nikolaos K., Fuks, Christin, Fürtig, Boris, Gallo, Angelo, Gande, Santosh L., Gerez, Juan Atilio, Gorbatyuk, Oksana, Guseva, Serafima, Hacker, Carolin, Häfner, Sabine, Hao, Bing, Hargittay, Bruno, Henzler-Wildman, K., Hoch, Jeffrey C., Malki, Anas, Hohmann, Katharina F., Hutchison, Marie T., Jaudzems, Kristaps, Jović, Katarina, Kaderli, Janina, Kalniņš, Gints, Kaņepe, Iveta, Kirchdoerfer, Robert N., Kirkpatrick, John, Knapp, Stefan, Bessa, Luiza Mamigonian, Krishnathas, Robin, Kutz, Felicitas, Lage, Susanne zur, Lambertz, Roderick, Lang, Andras, Laurents, Douglas V., Lecoq, Lauriane, Linhard, Verena, Löhr, Frank, Martin, Rachel W., Matzel, Tobias, Maurin, Damien, McNutt, Seth W., Mebus-Antunes, Nathane Cunha, Meier, Beat H., Meiser, Nathalie, Mompeán, Miguel, Pinheiro, Anderson S.., Monaca, Elisa, Montserret, Roland, Mariño Perez, Laura, Moser, Celine, Muhle-Goll, Claudia, Neves-Martins, Thais Cristtina, Ni, Xiamonin, Norton-Baker, Brenna, Pierattelli, Roberta, Pontoriero, Letizia, Sabbatella, Raffaele, Pustovalova, Yulia, Ohlenschläger, Oliver, Orts, Julien, Da Poian, Andrea T., Pyper, Dennis J., Richter, Christian, Riek, Roland, Rienstra, Chad M., Robertson, Angus, Salvi, Nicola, Saxena, Krishna, Schulte, Linda, Schiavina, Marco, Schwalbe, Harald, Silber, Mara, Silva Almeida, Marcius da, Sprague-Piercy, Marc A., Anderson, Thomas K., Spyroulias, Georgios A., Sreeramulu, Sridhar, Tants, Jan-Niklas, Tārs, Kaspars, Torres, Felix, Töws, Sabrina, Treviño, Miguel A., Trucks, Sven, Tsika, Aikaterini C., Varga, Krisztina, Anobom, Cristiane D., Wang, Ying, Weber, Marco E., Weigand, Julia E., Wiedemann, Christoph, Wirmer-Bartoschek, Julia, Wirtz Martin, Maria Alexandra, Zehnder, Johannes, Hengesbach, Martin, Schlundt, Andreas, Goethe University Frankfurt am Main, German Research Foundation, Cassa di Risparmio di Firenze, European Commission, University of New Hampshire, The Free State of Thuringia, National Institutes of Health (US), National Science Foundation (US), Howard Hughes Medical Institute, Latvian Council of Science, Ministry of Development and Investments (Greece), Helmholtz Association, Centre National de la Recherche Scientifique (France), Agence Nationale de la Recherche (France), Fondation pour la Recherche Médicale, Swiss National Science Foundation, Fonds National Suisse de la Recherche Scientifique, ETH Zurich, European Research Council, Université Grenoble Alpes, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación la Caixa, Instituto de Salud Carlos III, Boehringer Ingelheim Fonds, Ministero dell'Istruzione, dell'Università e della Ricerca, Polytechnic Foundation of Frankfurt am Main, Altincekic, Nadide, Korn, Sophie Marianne, Qureshi, Nusrat Shahin, Dujardin, Marie, Ninot-Pedrosa, Martí, Abele, Rupert, Abi Saad, Marie Jose, Alfano, Caterina, Almeida, Fabio C. L., Alshamleh, Islam, Cardoso de Amorim, Gisele, Anorma, Chelsea, Bains, Jasleen Kaur, Bax, Andriaan, Blackledge, Martin, Blechar, Julius, Böckmann, Anja, Brigandat, Louis, Bula, Anna, Bütikofer, Matthias, Camacho-Zarco, Aldo R., Ghosh, Dhiman, Carlomagno, Teresa, Caruso, Icaro Putinhon, Ceylan, Betül, Chaikuad, Apirat, Chu, Feixia, Cole, Laura, Crosby, Marquise G., Jesus, Vanessa de, Dhamotharan, Karthikeyan, Felli, Isabella C., Gomes-Neto, Francisco, Ferner, Jan, Fleischmann, Yanick, Fogeron, Marie-Laure, Fourkiotis, Nikolaos K., Fuks, Christin, Fürtig, Boris, Gallo, Angelo, Gande, Santosh L., Gerez, Juan Atilio, Gorbatyuk, Oksana, Guseva, Serafima, Hacker, Carolin, Häfner, Sabine, Hao, Bing, Hargittay, Bruno, Henzler-Wildman, K., Hoch, Jeffrey C., Malki, Anas, Hohmann, Katharina F., Hutchison, Marie T., Jaudzems, Kristaps, Jović, Katarina, Kaderli, Janina, Kalniņš, Gints, Kaņepe, Iveta, Kirchdoerfer, Robert N., Kirkpatrick, John, Knapp, Stefan, Bessa, Luiza Mamigonian, Krishnathas, Robin, Kutz, Felicitas, Lage, Susanne zur, Lambertz, Roderick, Lang, Andras, Laurents, Douglas V., Lecoq, Lauriane, Linhard, Verena, Löhr, Frank, Martin, Rachel W., Matzel, Tobias, Maurin, Damien, McNutt, Seth W., Mebus-Antunes, Nathane Cunha, Meier, Beat H., Meiser, Nathalie, Mompeán, Miguel, Pinheiro, Anderson S.., Monaca, Elisa, Montserret, Roland, Mariño Perez, Laura, Moser, Celine, Muhle-Goll, Claudia, Neves-Martins, Thais Cristtina, Ni, Xiamonin, Norton-Baker, Brenna, Pierattelli, Roberta, Pontoriero, Letizia, Sabbatella, Raffaele, Pustovalova, Yulia, Ohlenschläger, Oliver, Orts, Julien, Da Poian, Andrea T., Pyper, Dennis J., Richter, Christian, Riek, Roland, Rienstra, Chad M., Robertson, Angus, Salvi, Nicola, Saxena, Krishna, Schulte, Linda, Schiavina, Marco, Schwalbe, Harald, Silber, Mara, Silva Almeida, Marcius da, Sprague-Piercy, Marc A., Anderson, Thomas K., Spyroulias, Georgios A., Sreeramulu, Sridhar, Tants, Jan-Niklas, Tārs, Kaspars, Torres, Felix, Töws, Sabrina, Treviño, Miguel A., Trucks, Sven, Tsika, Aikaterini C., Varga, Krisztina, Anobom, Cristiane D., Wang, Ying, Weber, Marco E., Weigand, Julia E., Wiedemann, Christoph, Wirmer-Bartoschek, Julia, Wirtz Martin, Maria Alexandra, Zehnder, Johannes, Hengesbach, Martin, and Schlundt, Andreas

Abstract

The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.

Published
2021

32. Pingo Canadian Landmark. Ultra high resolution orthomosaic

Author

Vieira, Gonçalo, Pina, Pedro, Whalen, Dustin, Freitas, Pedro, Pinheiro, Daniel, Fraser, Paul, Robertson, Angus, and Berry, Heather B.

Subjects
Pingo Canadian Landmark, Permafrost, Tuktoyaktuk, Tundra, Coastal dynamics
Abstract

Ultra high resolution orthomosaic (Poster A0) of Pingo Canadian Landmark surveyed in July-August 2019.

Published
2020
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33. Tuktoyaktuk. Ultra high resolution orthomosaic

Author

Vieira, Gonçalo, Pina, Pedro, Whalen, Dustin, Freitas, Pedro, Pinheiro, Daniel, Malenfant, François, Fraser, Paul, Robertson, Angus, and Berry, Heather B.

Subjects
Infrastructure, Coastal, Tuktoyaktuk, Urban, Permafrost
Abstract

Aerial orthomosaic of the hamlet of Tuktoyaktuk - Poster A0. Survey conducted in July/August of 2018 and 2019 using a Sensefly ebee and a Sensefly ebee RTK Plus. Spatial resolution 10 cm.

Published
2020
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36. Advances in NMR Spectroscopy of Weakly Aligned Biomolecular Systems.

Author

Chiliveri, Sai Chaitanya, Robertson, Angus J., Shen, Yang, Torchia, Dennis A., and Bax, Ad

Abstract

The measurement and application of residual dipolar couplings (RDCs) in solution NMR studies of biological macromolecules has become well established over the past quarter of a century. Numerous methods for generating the requisite anisotropic orientational molecular distribution have been demonstrated, each with its specific strengths and weaknesses. In parallel, an enormous number of pulse schemes have been introduced to measure the many different types of RDCs, ranging from the most widely measured backbone amide 15N–1H RDCs, to 1H–1H RDCs and couplings between low-γ nuclei. Applications of RDCs range from structure validation and refinement to the determination of relative domain orientations, the measurement of backbone and domain motions, and de novo structure determination. Nevertheless, it appears that the power of the RDC methodology remains underutilized. This review aims to highlight the practical aspects of sample preparation and RDC measurement while describing some of the most straightforward applications that take advantage of the exceptionally precise information contained in such data. Some emphasis will be placed on more recent developments that enable the accurate measurement of RDCs in larger systems, which is key to the ongoing shift in focus of biological NMR spectroscopy from structure determination toward gaining improved understanding of how molecular flexibility drives protein function. [ABSTRACT FROM AUTHOR]

Published
2022
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45. van der Waals Contact between Nucleophile and Transferring Phosphorus Is Insufficient To Achieve Enzyme Transition-State Architecture

Author

Johnson, Luke A., primary, Robertson, Angus J., additional, Baxter, Nicola J., additional, Trevitt, Clare R., additional, Bisson, Claudine, additional, Jin, Yi, additional, Wood, Henry P., additional, Hounslow, Andrea M., additional, Cliff, Matthew J., additional, Blackburn, G. Michael, additional, Bowler, Matthew W., additional, and Waltho, Jonathan P., additional

Published
2018
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47. Probing the quality control mechanism of the Escherichia coli twin-arginine translocase with folding variants of a de novo–designed heme protein

Author

Sutherland, George A., primary, Grayson, Katie J., additional, Adams, Nathan B.P., additional, Mermans, Daphne M.J., additional, Jones, Alexander S., additional, Robertson, Angus J., additional, Auman, Dirk B., additional, Brindley, Amanda A., additional, Sterpone, Fabio, additional, Tuffery, Pierre, additional, Derreumaux, Philippe, additional, Dutton, P. Leslie, additional, Robinson, Colin, additional, Hitchcock, Andrew, additional, and Hunter, C. Neil, additional

Published
2018
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48. Anatomy for Problem Solving in Sports Medicine

Author

Harris, Philip, Robertson, Angus, Ranson, Craig, Harris, Philip, Robertson, Angus, and Ranson, Craig

Subjects
Sports injuries, Knee--Anatomy, Knee--Wounds and injuries
Abstract

When examining patients with sports-related and exercise-related injuries, a thorough knowledge of anatomy is vital in order to make an accurate diagnosis and work out an effective treatment plan. In this helpful, practical book, a professional anatomist, an orthopaedic surgeon and a sports physiotherapist have combined their expertise to give a detailed explanation of the structural and functional anatomy of the knee. The book includes descriptions and images of the relevant anatomy, and sample clinical problems (with model answers) throughout. Although each problem is different, practitioners will always follow a similar pattern in arriving at a differential diagnosis. In every case, four main areas need to be covered: the type of sport; the clinical history; physical assessment; and appropriate investigations. By taking a logical, step-by-step approach to solving clinical problems, this book offers a valuable resource for the wide range of health professionals who manage knee injuries.

Published
2014

50. Two-site recognition of Staphylococcus aureuspeptidoglycan by lysostaphin SH3b

Author

Gonzalez-Delgado, Luz S., Walters-Morgan, Hannah, Salamaga, Bartłomiej, Robertson, Angus J., Hounslow, Andrea M., Jagielska, Elżbieta, Sabała, Izabela, Williamson, Mike P., Lovering, Andrew L., and Mesnage, Stéphane

Abstract

Lysostaphin is a bacteriolytic enzyme targeting peptidoglycan, the essential component of the bacterial cell envelope. It displays a very potent and specific activity toward staphylococci, including methicillin-resistant Staphylococcus aureus. Lysostaphin causes rapid cell lysis and disrupts biofilms, and is therefore a therapeutic agent of choice to eradicate staphylococcal infections. The C-terminal SH3b domain of lysostaphin recognizes peptidoglycans containing a pentaglycine crossbridge and has been proposed to drive the preferential digestion of staphylococcal cell walls. Here we elucidate the molecular mechanism underpinning recognition of staphylococcal peptidoglycan by the lysostaphin SH3b domain. We show that the pentaglycine crossbridge and the peptide stem are recognized by two independent binding sites located on opposite sides of the SH3b domain, thereby inducing a clustering of SH3b domains. We propose that this unusual binding mechanism allows synergistic and structurally dynamic recognition of S. aureuspeptidoglycan and underpins the potent bacteriolytic activity of this enzyme.

Published
2020
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