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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. Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections

Author

Reinke, Patrick Y. A., de Souza, Edmarcia Elisa, Günther, Sebastian, Falke, Sven, Lieske, Julia, Ewert, Wiebke, Loboda, Jure, Herrmann, Alexander, Rahmani Mashhour, Aida, Karničar, Katarina, Usenik, Aleksandra, Lindič, Nataša, Sekirnik, Andreja, Botosso, Viviane Fongaro, Santelli, Gláucia Maria Machado, Kapronezai, Josana, de Araújo, Marcelo Valdemir, Silva-Pereira, Taiana Tainá, Filho, Antônio Francisco de Souza, Tavares, Mariana Silva, Flórez-Álvarez, Lizdany, de Oliveira, Danielle Bruna Leal, Durigon, Edison Luiz, Giaretta, Paula Roberta, Heinemann, Marcos Bryan, Hauser, Maurice, Seychell, Brandon, Böhler, Hendrik, Rut, Wioletta, Drag, Marcin, Beck, Tobias, Cox, Russell, Chapman, Henry N., Betzel, Christian, Brehm, Wolfgang, Hinrichs, Winfried, Ebert, Gregor, Latham, Sharissa L., Guimarães, Ana Marcia de Sá, Turk, Dusan, Wrenger, Carsten, and Meents, Alke

Published
2023
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4. Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease

Author

Srinivasan, Vasundara, Brognaro, Hévila, Prabhu, Prince R., de Souza, Edmarcia Elisa, Günther, Sebastian, Reinke, Patrick Y. A., Lane, Thomas J., Ginn, Helen, Han, Huijong, Ewert, Wiebke, Sprenger, Janina, Koua, Faisal H. M., Falke, Sven, Werner, Nadine, Andaleeb, Hina, Ullah, Najeeb, Franca, Bruno Alves, Wang, Mengying, Barra, Angélica Luana C., Perbandt, Markus, Schwinzer, Martin, Schmidt, Christina, Brings, Lea, Lorenzen, Kristina, Schubert, Robin, Machado, Rafael Rahal Guaragna, Candido, Erika Donizette, Oliveira, Danielle Bruna Leal, Durigon, Edison Luiz, Niebling, Stephan, Garcia, Angelica Struve, Yefanov, Oleksandr, Lieske, Julia, Gelisio, Luca, Domaracky, Martin, Middendorf, Philipp, Groessler, Michael, Trost, Fabian, Galchenkova, Marina, Mashhour, Aida Rahmani, Saouane, Sofiane, Hakanpää, Johanna, Wolf, Markus, Alai, Maria Garcia, Turk, Dusan, Pearson, Arwen R., Chapman, Henry N., Hinrichs, Winfried, Wrenger, Carsten, Meents, Alke, and Betzel, Christian

Published
2022
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5. Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors

Author

Falke, Sven, primary, Lieske, Julia, additional, Herrmann, Alexander, additional, Loboda, Jure, additional, Karničar, Katarina, additional, Günther, Sebastian, additional, Reinke, Patrick Y. A., additional, Ewert, Wiebke, additional, Usenik, Aleksandra, additional, Lindič, Nataša, additional, Sekirnik, Andreja, additional, Dretnik, Klemen, additional, Tsuge, Hideaki, additional, Turk, Vito, additional, Chapman, Henry N., additional, Hinrichs, Winfried, additional, Ebert, Gregor, additional, Turk, Dušan, additional, and Meents, Alke, additional

Published
2024
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6. Structural and Biochemical Characterization of a Dye-Decolorizing Peroxidase from Dictyostelium discoideum

Author

Rai, Amrita, Klare, Johann P., Reinke, Patrick Y. A., Englmaier, Felix, Fohrer, Jörg, Fedorov, Roman, Taft, Manuel H., Chizhov, Igor, Curth, Ute, Plettenburg, Oliver, Manstein, Dietmar J., Rai, Amrita, Klare, Johann P., Reinke, Patrick Y. A., Englmaier, Felix, Fohrer, Jörg, Fedorov, Roman, Taft, Manuel H., Chizhov, Igor, Curth, Ute, Plettenburg, Oliver, and Manstein, Dietmar J.

Abstract

A novel cytoplasmic dye-decolorizing peroxidase from Dictyostelium discoideum was investigated that oxidizes anthraquinone dyes, lignin model compounds, and general peroxidase substrates such as ABTS efficiently. Unlike related enzymes, an aspartate residue replaces the first glycine of the conserved GXXDG motif in Dictyostelium DyPA. In solution, Dictyostelium DyPA exists as a stable dimer with the side chain of Asp146 contributing to the stabilization of the dimer interface by extending the hydrogen bond network connecting two monomers. To gain mechanistic insights, we solved the Dictyostelium DyPA structures in the absence of substrate as well as in the presence of potassium cyanide and veratryl alcohol to 1.7, 1.85, and 1.6 Å resolution, respectively. The active site of Dictyostelium DyPA has a hexa-coordinated heme iron with a histidine residue at the proximal axial position and either an activated oxygen or CN⁻ molecule at the distal axial position. Asp149 is in an optimal conformation to accept a proton from H₂O₂ during the formation of compound I. Two potential distal solvent channels and a conserved shallow pocket leading to the heme molecule were found in Dictyostelium DyPA. Further, we identified two substrate-binding pockets per monomer in Dictyostelium DyPA at the dimer interface. Long-range electron transfer pathways associated with a hydrogen-bonding network that connects the substrate-binding sites with the heme moiety are described.

Published
2024

7. Structural elucidation and antiviral activity of cathepsin L inhibitors with carbonyl and epoxide warheads

Author

Falke, Sven, primary, Lieske, Julia, additional, Herrmann, Alexander, additional, Loboda, Jure, additional, Gunther, Sebastian, additional, Reinke, Patrick Y A, additional, Ewert, Wiebke, additional, Karnicar, Katarina, additional, Usenik, Aleksandra, additional, Lindic, Natasa, additional, Sekirnik, Andreja, additional, Tsuge, Hideaki, additional, Turk, Vito, additional, Chapman, Henry N, additional, Hinrichs, Winfried, additional, Ebert, Gregor, additional, Turk, Dusan, additional, and Meents, Alke, additional

Published
2023
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9. Time-resolved crystallography captures light-driven DNA repair.

Author

Christou, Nina-Eleni, Apostolopoulou, Virginia, Melo, Diogo V. M., Ruppert, Matthias, Fadini, Alisia, Henkel, Alessandra, Sprenger, Janina, Oberthuer, Dominik, Günther, Sebastian, Pateras, Anastasios, Mashhour, Aida Rahmani, Yefanov, Oleksandr M., Galchenkova, Marina, Reinke, Patrick Y. A., Kremling, Viviane, Scheer, T. Emilie S., Lange, Esther R., Middendorf, Philipp, Schubert, Robin, and Zitter, Elke De

Published
2023
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10. Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia

Author

Latham, Sharissa L., Ehmke, Nadja, Reinke, Patrick Y. A., Taft, Manuel H., Eicke, Dorothee, Reindl, Theresia, Stenzel, Werner, Lyons, Michael J., Friez, Michael J., Lee, Jennifer A., Hecker, Ramona, Frühwald, Michael C., Becker, Kerstin, Neuhann, Teresa M., Horn, Denise, Schrock, Evelin, Niehaus, Indra, Sarnow, Katharina, Grützmann, Konrad, Gawehn, Luzie, Klink, Barbara, Rump, Andreas, Chaponnier, Christine, Figueiredo, Constanca, Knöfler, Ralf, Manstein, Dietmar J., and Di Donato, Nataliya

Published
2018
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11. Author Correction: Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia

Author

Latham, Sharissa L., Ehmke, Nadja, Reinke, Patrick Y. A., Taft, Manuel H., Eicke, Dorothee, Reindl, Theresia, Stenzel, Werner, Lyons, Michael J., Friez, Michael J., Lee, Jennifer A., Hecker, Ramona, Frühwald, Michael C., Becker, Kerstin, Neuhann, Teresa M., Horn, Denise, Schrock, Evelin, Niehaus, Indra, Sarnow, Katharina, Grützmann, Konrad, Gawehn, Luzie, Klink, Barbara, Rump, Andreas, Chaponnier, Christine, Figueiredo, Constanca, Knöfler, Ralf, Manstein, Dietmar J., and Di Donato, Nataliya

Published
2018
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12. Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease

Author

Ewert, Wiebke, primary, Günther, Sebastian, additional, Miglioli, Francesca, additional, Falke, Sven, additional, Reinke, Patrick Y. A., additional, Niebling, Stephan, additional, Günther, Christian, additional, Han, Huijong, additional, Srinivasan, Vasundara, additional, Brognaro, Hévila, additional, Lieske, Julia, additional, Lorenzen, Kristina, additional, Garcia-Alai, Maria M., additional, Betzel, Christian, additional, Carcelli, Mauro, additional, Hinrichs, Winfried, additional, Rogolino, Dominga, additional, and Meents, Alke, additional

Published
2022
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13. Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease

Author

Ewert, Wiebke, Günther, Sebastian, Miglioli, Francesca, Falke, Sven, Reinke, Patrick Y. A., Niebling, Stephan, Guenther, Christian, Han, Huijong, Srinivasan, Vasundara, Brognaro, Hévila, Lieske, Julia, Lorenzen, Kristina, Garcia-Alai, Maria M., Betzel, Christian, Carcelli, Mauro, Hinrichs, Winfried, Rogolino, Dominga, and Meents, Alke

Subjects
ddc:540
Abstract

Frontiers in Chemistry 10, 832431 (2022). doi:10.3389/fchem.2022.832431, The papain-like protease (PLpro) of SARS-CoV-2 is essential for viral propagation and, additionally, dysregulation of the host innate immune system. Using a library of 40 potential metal-chelating compounds we performed an X-ray crystallographic screening against PLpro. As outcome we identified six compounds binding to the target protein. Here we describe the interaction of one hydrazone (H1) and five thiosemicarbazone (T1-T5) compounds with the two distinct natural substrate binding sites of PLpro for ubiquitin and ISG15. H1 binds to a polar groove at the S1 binding site by forming several hydrogen bonds with PLpro. T1-T5 bind into a deep pocket close to the polyubiquitin and ISG15 binding site S2. Their interactions are mainly mediated by multiple hydrogen bonds and further hydrophobic interactions. In particular compound H1 interferes with natural substrate binding by sterical hindrance and induces conformational changes in protein residues involved in substrate binding, while compounds T1-T5 could have a more indirect effect. Fluorescence based enzyme activity assay and complementary thermal stability analysis reveal only weak inhibition properties in the high micromolar range thereby indicating the need for compound optimization. Nevertheless, the unique binding properties involving strong hydrogen bonding and the various options for structural optimization make the compounds ideal lead structures. In combination with the inexpensive and undemanding synthesis, the reported hydrazone and thiosemicarbazones represent an attractive scaffold for further structure-based development of novel PLpro inhibitors by interrupting protein-protein interactions at the S1 and S2 site., Published by Frontiers Media, Lausanne

Published
2022
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14. SARS-CoV-2 papain-like protease PLpro in complex with natural compounds reveal allosteric sites for antiviral drug design

Author

Srinivasan, Vasundara, primary, Brognaro, Hévila, additional, Prabhu, Prince R., additional, de Souza, Edmarcia Elisa, additional, Günther, Sebastian, additional, Reinke, Patrick Y. A., additional, Lane, Thomas J., additional, Ginn, Helen, additional, Han, Huijong, additional, Ewert, Wiebke, additional, Sprenger, Janina, additional, Koua, Faisal H. M., additional, Falke, Sven, additional, Werner, Nadine, additional, Andaleeb, Hina, additional, Ullah, Najeeb, additional, Franca, Bruno Alves, additional, Wang, Mengying, additional, Barra, Angélica Luana C, additional, Perbandt, Markus, additional, Schwinzer, Martin, additional, Schmidt, Christina, additional, Brings, Lea, additional, Lorenzen, Kristina, additional, Schubert, Robin, additional, Guaragna Machado, Rafael Rahal, additional, Candido, Erika Donizette, additional, Leal Oliveira, Danielle Bruna, additional, Durigon, Edison Luiz, additional, Yefanov, Oleksandr, additional, Lieske, Julia, additional, Gelisio, Luca, additional, Domaracky, Martin, additional, Middendorf, Philipp, additional, Groessler, Michael, additional, Trost, Fabian, additional, Galchenkova, Marina, additional, Saouane, Sofiane, additional, Hakanpää, Johanna, additional, Wolf, Markus, additional, Turk, Dusan, additional, Pearson, Arwen R., additional, Chapman, Henry N., additional, Hinrichs, Winfried, additional, Wrenger, Carsten, additional, Meents, Alke, additional, and Betzel, Christian, additional

Published
2021
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16. Structural and Biochemical Characterization of a Dye-Decolorizing Peroxidase from Dictyostelium discoideum

Author

Rai, Amrita, Klare, Johann P., Reinke, Patrick Y. A., Englmaier, Felix, Fohrer, Jörg, Fedorov, Roman, Taft, Manuel H., Chizhov, Igor, Curth, Ute, Plettenburg, Oliver, Manstein, Dietmar J., Rai, Amrita, Klare, Johann P., Reinke, Patrick Y. A., Englmaier, Felix, Fohrer, Jörg, Fedorov, Roman, Taft, Manuel H., Chizhov, Igor, Curth, Ute, Plettenburg, Oliver, and Manstein, Dietmar J.

Abstract

A novel cytoplasmic dye-decolorizing peroxidase from Dictyostelium discoideum was investi-gated that oxidizes anthraquinone dyes, lignin model compounds, and general peroxidase substrates such as ABTS efficiently. Unlike related enzymes, an aspartate residue replaces the first glycine of the conserved GXXDG motif in Dictyostelium DyPA. In solution, Dictyostelium DyPA exists as a stable dimer with the side chain of Asp146 contributing to the stabilization of the dimer interface by extending the hydrogen bond network connecting two monomers. To gain mechanistic insights, we solved the Dicty-ostelium DyPA structures in the absence of substrate as well as in the presence of potassium cyanide and veratryl alcohol to 1.7, 1.85, and 1.6 Å resolution, respectively. The active site of Dictyostelium DyPA has a hexa-coordinated heme iron with a histidine residue at the proximal axial position and either an acti-vated oxygen or CN− molecule at the distal axial position. Asp149 is in an optimal conformation to accept a proton from H2O2 during the formation of compound I. Two potential distal solvent channels and a conserved shallow pocket leading to the heme molecule were found in Dictyostelium DyPA. Further, we identified two substrate-binding pockets per monomer in Dictyostelium DyPA at the dimer interface. Long-range electron transfer pathways associated with a hydrogen-bonding network that connects the substrate-binding sites with the heme moiety are described.

Published
2021

17. 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

18. 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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19. 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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20. 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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21. N-terminal splicing extensions of the human MYO1C gene fine-tune the kinetics of the three full-length myosin IC isoforms

Author

Zattelman, Lilach, Regev, Ronit, Ušaj, Marko, Reinke, Patrick Y. A., Giese, Sven, Samson, Abraham O., Taft, Manuel H., Manstein, Dietmar J., Henn, Arnon, Zattelman, Lilach, Regev, Ronit, Ušaj, Marko, Reinke, Patrick Y. A., Giese, Sven, Samson, Abraham O., Taft, Manuel H., Manstein, Dietmar J., and Henn, Arnon

Abstract

The MYO1C gene produces three alternatively spliced isoforms, differing only in their N-terminal regions (NTRs). These isoforms, which exhibit both specific and overlapping nuclear and cytoplasmic functions, have different expression levels and nuclear–cytoplasmic partitioning. To investigate the effect of NTR extensions on the enzymatic behavior of individual isoforms, we overexpressed and purified the three full-length human isoforms from suspension-adapted HEK cells. MYO1CC favored the actomyosin closed state (AMC), MYO1C16 populated the actomyosin open state (AMO) and AMC equally, and MYO1C35 favored the AMO state. Moreover, the full-length constructs isomerized before ADP release, which has not been observed previously in truncated MYO1CC constructs. Furthermore, global numerical simulation analysis predicted that MYO1C35 populated the actomyosin·ADP closed state (AMDC) 5-fold more than the actomyosin·ADP open state (AMDO) and to a greater degree than MYO1CC and MYO1C16 (4- and 2-fold, respectively). On the basis of a homology model of the 35-amino acid NTR of MYO1C35 (NTR35) docked to the X-ray structure of MYO1CC, we predicted that MYO1C35 NTR residue Arg-21 would engage in a specific interaction with post-relay helix residue Glu-469, which affects the mechanics of the myosin power stroke. In addition, we found that adding the NTR35 peptide to MYO1CC yielded a protein that transiently mimics MYO1C35 kinetic behavior. By contrast, NTR35, which harbors the R21G mutation, was unable to confer MYO1C35-like kinetic behavior. Thus, the NTRs affect the specific nucleotide-binding properties of MYO1C isoforms, adding to their kinetic diversity. We propose that this level of fine-tuning within MYO1C broadens its adaptability within cells.

Published
2017
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22. 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

23. 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

24. Mechanochemical properties of human myosin-1C are modulated by isoform-specific differences in the N-terminal extension.

Author

Giese, Sven, Reindl, Theresia, Reinke, Patrick Y. A., Zattelman, Lilach, Fedorov, Roman, Henn, Arnon, Taft, Manuel H., and Manstein, Dietmar J.

Subjects
*MYOSIN, *BILAYER lipid membranes, *RESISTIVE force, *GENETIC engineering, *HUMAN beings, *CYTOSOL
Abstract

Myosin-1C is a single-headed, short-tailed member of the myosin class I subfamily that supports a variety of actin-based functions in the cytosol and nucleus. In vertebrates, alternative splicing of the MYO1C gene leads to the production of three isoforms, myosin-1C0, myosin-1C16, and myosin-1C35, that carry N-terminal extensions of different lengths. However, it is not clear how these extensions affect the chemomechanical coupling of human myosin-1C isoforms. Here, we report on the motor activity of the different myosin-1C isoforms measuring the unloaded velocities of constructs lacking the C-terminal lipid-binding domain on nitrocellulose-coated glass surfaces and full-length constructs on reconstituted, supported lipid bilayers. The higher yields of purified proteins obtained with constructs lacking the lipid-binding domain allowed a detailed characterization of the individual kinetic steps of human myosin-1C isoforms in their productive interaction with nucleotides and filamentous actin. Isoform-specific differences include 18-fold changes in the maximum power output per myosin-1C motor and 4-fold changes in the velocity and the resistive force at which maximum power output occurs. Our results support a model in which the isoform-specific N-terminal extensions affect chemomechanical coupling by combined steric and allosteric effects, thereby reducing both the length of the working stroke and the rate of ADP release in the absence of external loads by a factor of 2 for myosin-1C35. As the large change in maximum power output shows, the functional differences between the isoforms are further amplified by the presence of external load. [ABSTRACT FROM AUTHOR]

Published
2021
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25. Crystal structures of cables formed by the acetylated and unacetylated forms of the Schizosaccharomyces pombe tropomyosin orthologue Tpm Cdc8 .

Author

Reinke PYA, Heiringhoff RS, Reindl T, Baker K, Taft MH, Meents A, Mulvihill DP, Davies OR, Fedorov R, Zahn M, and Manstein DJ

Abstract

Cables formed by head-to-tail polymerization of tropomyosin, localized along the length of sarcomeric and cytoskeletal actin filaments, play a key role in regulating a wide range of motile and contractile processes. The stability of tropomyosin cables, their interaction with actin filaments and the functional properties of the resulting co-filaments are thought to be affected by N-terminal acetylation of tropomyosin. Here, we present high-resolution structures of cables formed by acetylated and unacetylated Schizosaccharomyces pombe tropomyosin orthologue Tpm Cdc8 . The crystal structures represent different types of cables, each consisting of Tpm Cdc8 homodimers in a different conformation. The structures show how the interactions of the residues in the overlap junction contribute to cable formation and how local structural perturbations affect the conformational dynamics of the protein and its ability to transmit allosteric signals. In particular, N-terminal acetylation increases the helicity of the adjacent region, which leads to a local reduction in conformational dynamics and consequently to less fraying of the N-terminal region. This creates a more consistent complementary surface facilitating the formation of specific interactions across the overlap junction., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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26. N-terminal splicing extensions of the human MYO1C gene fine-tune the kinetics of the three full-length myosin IC isoforms.

Author

Zattelman L, Regev R, Ušaj M, Reinke PYA, Giese S, Samson AO, Taft MH, Manstein DJ, and Henn A

Subjects
Actomyosin chemistry, Actomyosin genetics, Actomyosin metabolism, Adenosine Diphosphate chemistry, Adenosine Diphosphate genetics, Adenosine Diphosphate metabolism, Amino Acid Substitution, Crystallography, X-Ray, HEK293 Cells, Humans, Isoenzymes, Mutation, Missense, Alternative Splicing, Myosin Type I chemistry, Myosin Type I genetics, Myosin Type I metabolism
Abstract

The MYO1C gene produces three alternatively spliced isoforms, differing only in their N-terminal regions (NTRs). These isoforms, which exhibit both specific and overlapping nuclear and cytoplasmic functions, have different expression levels and nuclear-cytoplasmic partitioning. To investigate the effect of NTR extensions on the enzymatic behavior of individual isoforms, we overexpressed and purified the three full-length human isoforms from suspension-adapted HEK cells. MYO1C C favored the actomyosin closed state (AM C ), MYO1C 16 populated the actomyosin open state (AM O ) and AM C equally, and MYO1C 35 favored the AM O state. Moreover, the full-length constructs isomerized before ADP release, which has not been observed previously in truncated MYO1C C constructs. Furthermore, global numerical simulation analysis predicted that MYO1C 35 populated the actomyosin·ADP closed state (AMD C ) 5-fold more than the actomyosin·ADP open state (AMD O ) and to a greater degree than MYO1C C and MYO1C 16 (4- and 2-fold, respectively). On the basis of a homology model of the 35-amino acid NTR of MYO1C 35 (NTR 35 ) docked to the X-ray structure of MYO1C C , we predicted that MYO1C 35 NTR residue Arg-21 would engage in a specific interaction with post-relay helix residue Glu-469, which affects the mechanics of the myosin power stroke. In addition, we found that adding the NTR 35 peptide to MYO1C C yielded a protein that transiently mimics MYO1C 35 kinetic behavior. By contrast, NTR 35 , which harbors the R21G mutation, was unable to confer MYO1C 35 -like kinetic behavior. Thus, the NTRs affect the specific nucleotide-binding properties of MYO1C isoforms, adding to their kinetic diversity. We propose that this level of fine-tuning within MYO1C broadens its adaptability within cells., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Published
2017
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