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2. Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia

Author

Marchesini, Matteo, Gherli, Andrea, Montanaro, Anna, Patrizi, Laura, Sorrentino, Claudia, Pagliaro, Luca, Rompietti, Chiara, Kitara, Samuel, Heit, Sabine, Olesen, Claus E., Møller, Jesper V., Savi, Monia, Bocchi, Leonardo, Vilella, Rocchina, Rizzi, Federica, Baglione, Marilena, Rastelli, Giorgia, Loiacono, Caterina, La Starza, Roberta, Mecucci, Cristina, Stegmaier, Kimberly, Aversa, Franco, Stilli, Donatella, Lund Winther, Anne-Marie, Sportoletti, Paolo, Bublitz, Maike, Dalby-Brown, William, and Roti, Giovanni

Published
2020
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3. Antibodies toward Na+,HCO3–-cotransporter NBCn1/SLC4A7 block net acid extrusion and cause pH-dependent growth inhibition and apoptosis in breast cancer.

Author

Axelsen, Trine V., Olesen, Claus, Khan, Danish, Mohammadi, Ali, Bouzinova, Elena V., Nielsen, Christine J. F., Mele, Marco, Hauerslev, Katrine R., Pedersen, Helene L., Balling, Eva, Vahl, Pernille, Tramm, Trine, Christiansen, Peer M., and Boedtkjer, Ebbe

Abstract

Background: Na+,HCO3–-cotransporter NBCn1/Slc4a7 accelerates murine breast carcinogenesis. Lack of specific pharmacological tools previously restricted therapeutic targeting of NBCn1 and identification of NBCn1-dependent functions in human breast cancer. Methods: We develop extracellularly-targeted anti-NBCn1 antibodies, screen for functional activity on cells, and evaluate (a) mechanisms of intracellular pH regulation in human primary breast carcinomas, (b) proliferation, cell death, and tumor growth consequences of NBCn1 in triple-negative breast cancer, and (c) association of NBCn1-mediated Na+,HCO3–-cotransport with human breast cancer metastasis. Results: We identify high-affinity (KD ≈ 0.14 nM) anti-NBCn1 antibodies that block human NBCn1-mediated Na+,HCO3–-cotransport in cells, without cross-reactivity towards human NBCe1 or murine NBCn1. These anti-NBCn1 antibodies abolish Na+,HCO3–-cotransport activity in freshly isolated primary organoids from human breast carcinomas and lower net acid extrusion effectively in primary breast cancer tissue from patients with macrometastases in axillary lymph nodes. Inhibitory anti-NBCn1 antibodies decelerate tumor growth in vivo by ~50% in a patient-derived xenograft model of triple-negative breast cancer and pH-dependently reduce colony formation, cause G2/M-phase cell cycle accumulation, and increase apoptosis of metastatic triple-negative breast cancer cells in vitro. Conclusions: Inhibitory anti-NBCn1 antibodies block net acid extrusion in human breast cancer tissue, particularly from patients with disseminated disease, and pH-dependently limit triple-negative breast cancer growth. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Fungal NRPS-Dependent Siderophores: From Function to Prediction

Author

Sørensen, Jens Laurids, Knudsen, Michael, Hansen, Frederik Teilfeldt, Olesen, Claus, Fuertes, Patricia Romans, Lee, T. Verne, Sondergaard, Teis Esben, Pedersen, Christian Nørgaard Storm, Brodersen, Ditlev Egeskov, Giese, Henriette, Gupta, Vijai Kumar, Series editor, Tuohy, Maria G., Series editor, Martín, Juan-Francisco, editor, García-Estrada, Carlos, editor, and Zeilinger, Susanne, editor

Published
2014
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6. Structures of the heart specific SERCA2a Ca2+‐ATPase

Author

Sitsel, Aljona, De Raeymaecker, Joren, Drachmann, Nikolaj Düring, Derua, Rita, Smaardijk, Susanne, Andersen, Jacob Lauwring, Vandecaetsbeek, Ilse, Chen, Jialin, De Maeyer, Marc, Waelkens, Etienne, Olesen, Claus, Vangheluwe, Peter, and Nissen, Poul

Published
2019
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7. Invisible detergents for structure determination of membrane proteins by small‐angle neutron scattering

Author

Midtgaard, Søren Roi, Darwish, Tamim A., Pedersen, Martin Cramer, Huda, Pie, Larsen, Andreas Haahr, Jensen, Grethe Vestergaard, Kynde, Søren Andreas Røssell, Skar‐Gislinge, Nicholas, Nielsen, Agnieszka Janina Zygadlo, Olesen, Claus, Blaise, Mickael, Dorosz, Jerzy Józef, Thorsen, Thor Seneca, Venskutonytė, Raminta, Krintel, Christian, Møller, Jesper V., Frielinghaus, Henrich, Gilbert, Elliot Paul, Martel, Anne, Kastrup, Jette Sandholm, Jensen, Poul Erik, Nissen, Poul, and Arleth, Lise

Published
2018
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19. The structural basis of calcium transport by the calcium pump

Author

Olesen, Claus, Picard, Martin, Winther, Anne-Marie Lund, Gyrup, Claus, Morth, J. Preben, Oxvig, Claus, Moller, Jesper Vuust, and Nissen, Poul

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Claus Olesen [1, 2]; Martin Picard [3, 4]; Anne-Marie Lund Winther [1, 3]; Claus Gyrup [3]; J. Preben Morth [1, 3]; Claus Oxvig [3]; Jesper Vuust Møller (corresponding author) [...]

Published
2007
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20. Membrane-protein crystals for neutron diffraction

Author

Sørensen, Thomas Lykke-Møller, Hjorth-Jensen, Samuel John, Oksanen, Esko, Andersen, Jacob Lauwring, Olesen, Claus, Møller, Jesper Vuust, and Nissen, Poul

Subjects
Models, Molecular, 0301 basic medicine, Materials science, Protein Conformation, Neutron diffraction, Macromolecular crystallography, Nucleation, Crystallography, X-Ray, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Crystal, Neutron Diffraction, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Structural biology, Structural Biology, Chemical physics, Scientific method, Animals, Neutron source, Neutron, Rabbits, Crystallization, 030217 neurology & neurosurgery
Abstract

Neutron macromolecular crystallography (NMX) has the potential to provide the experimental input to address unresolved aspects of transport mechanisms and protonation in membrane proteins. However, despite this clear scientific motivation, the practical challenges of obtaining crystals that are large enough to make NMX feasible have so far been prohibitive. Here, the potential impact on feasibility of a more powerful neutron source is reviewed and a strategy for obtaining larger crystals is formulated, exemplified by the calcium-transporting ATPase SERCA1. The challenges encountered at the various steps in the process from crystal nucleation and growth to crystal mounting are explored, and it is demonstrated that NMX-compatible membrane-protein crystals can indeed be obtained.

Published
2018
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21. Tracking Ca2+ ATPase intermediates in real time by x-ray solution scattering

Author

Ravishankar, Harsha, Pedersen, Martin Nors, Eklund, Mattias, Sitsel, Aljona, Li, Chenge, Duelli, Annette, Levantino, Matteo, Wulff, Michael, Barth, Andreas, Olesen, Claus, Nissen, Poul, Andersson, Magnus, Ravishankar, Harsha, Pedersen, Martin Nors, Eklund, Mattias, Sitsel, Aljona, Li, Chenge, Duelli, Annette, Levantino, Matteo, Wulff, Michael, Barth, Andreas, Olesen, Claus, Nissen, Poul, and Andersson, Magnus

Abstract

Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) transporters regulate calcium signaling by active calcium ion reuptake to internal stores. Structural transitions associated with transport have been characterized by x-ray crystallography, but critical intermediates involved in the accessibility switch across the membrane are missing. We combined time-resolved x-ray solution scattering (TR-XSS) experiments and molecular dynamics (MD) simulations for real-time tracking of concerted SERCA reaction cycle dynamics in the native membrane. The equilibrium [Ca-2] E1 state before laser activation differed in the domain arrangement compared with crystal structures, and following laser-induced release of caged ATP, a 1.5-ms intermediate was formed that showed closure of the cytoplasmic domains typical of E1 states with bound Ca2+ and ATP. A subsequent 13-ms transient state showed a previously unresolved actuator (A) domain arrangement that exposed the ADP-binding site after phosphorylation. Hence, the obtained TR-XSS models determine the relative timing of so-far elusive domain rearrangements in a native environment.

Published
2020
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28. Experimental phasing with vanadium and application to nucleotide-binding membrane proteins

Author

El Omari, Kamel, primary, Mohamad, Nada, additional, Bountra, Kiran, additional, Duman, Ramona, additional, Romano, Maria, additional, Schlegel, Katja, additional, Kwong, Hok-Sau, additional, Mykhaylyk, Vitaliy, additional, Olesen, Claus, additional, Moller, Jesper Vuust, additional, Bublitz, Maike, additional, Beis, Konstantinos, additional, and Wagner, Armin, additional

Published
2020
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30. Tracking Ca 2+ ATPase intermediates in real time by x-ray solution scattering

Author

Ravishankar, Harsha, primary, Pedersen, Martin Nors, additional, Eklund, Mattias, additional, Sitsel, Aljona, additional, Li, Chenge, additional, Duelli, Annette, additional, Levantino, Matteo, additional, Wulff, Michael, additional, Barth, Andreas, additional, Olesen, Claus, additional, Nissen, Poul, additional, and Andersson, Magnus, additional

Published
2020
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33. Structures of the heart specific SERCA 2a Ca 2+ ‐ ATP ase

Author

Sitsel, Aljona, primary, De Raeymaecker, Joren, additional, Drachmann, Nikolaj Düring, additional, Derua, Rita, additional, Smaardijk, Susanne, additional, Andersen, Jacob Lauwring, additional, Vandecaetsbeek, Ilse, additional, Chen, Jialin, additional, De Maeyer, Marc, additional, Waelkens, Etienne, additional, Olesen, Claus, additional, Vangheluwe, Peter, additional, and Nissen, Poul, additional

Published
2019
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34. Membrane-protein crystals for neutron diffraction

Author

Sørensen, Thomas Lykke-Møller, primary, Hjorth-Jensen, Samuel John, additional, Oksanen, Esko, additional, Andersen, Jacob Lauwring, additional, Olesen, Claus, additional, Møller, Jesper Vuust, additional, and Nissen, Poul, additional

Published
2018
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35. Structures of the heart specific SERCA2a Ca2+-ATPase

Author

Sitsel, Aljona, primary, Raeymaecker, Joren De, additional, Drachmann, Nikolaj Düring, additional, Derua, Rita, additional, Smaardijk, Susanne, additional, Andersen, Jacob Lauwring, additional, Vandecaetsbeek, Ilse, additional, Chen, Jialin, additional, Maeyer, Marc De, additional, Waelkens, Etienne, additional, Olesen, Claus, additional, Vangheluwe, Peter, additional, and Nissen, Poul, additional

Published
2018
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37. Lipid exchange by ultracentrifugation

Author

Drachmann, Nikolaj Düring and Olesen, Claus

Subjects
lipid exchange, density gradient, SERCA, Membrane proteins, lipids (amino acids, peptides, and proteins), Synthetic lipids, Ultracentrifugation, Native lipids
Abstract

Lipids play an important role in maintaining P-type ATPase structure and function, and often they are crucial for ATPase activity. When the P-type ATPases are in the membrane, they are surrounded by a mix of different lipids species with varying aliphatic chain lengths and saturation, and the complex interplay between the lipids and the P-type ATPases are still not well understood. We here describe a robust method to exchange the majority of the lipids surrounding the ATPase after solubilisation and/or purification with a target lipid of interest. The method is based on an ultracentrifugation step, where the protein sample is spun through a dense buffer containing large excess of the target lipid, which results in an approximately 80-85 % lipid exchange. The method is a very gently technique that maintains protein folding during the process, hence allowing further characterization of the protein in the presence of a target lipid of interest.

Published
2016

38. Invisible detergents for structure determination of membrane proteins by small‐angle neutron scattering

Author

Midtgaard, Søren Roi, primary, Darwish, Tamim A., additional, Pedersen, Martin Cramer, additional, Huda, Pie, additional, Larsen, Andreas Haahr, additional, Jensen, Grethe Vestergaard, additional, Kynde, Søren Andreas Røssell, additional, Skar‐Gislinge, Nicholas, additional, Nielsen, Agnieszka Janina Zygadlo, additional, Olesen, Claus, additional, Blaise, Mickael, additional, Dorosz, Jerzy Józef, additional, Thorsen, Thor Seneca, additional, Venskutonytė, Raminta, additional, Krintel, Christian, additional, Møller, Jesper V., additional, Frielinghaus, Henrich, additional, Gilbert, Elliot Paul, additional, Martel, Anne, additional, Kastrup, Jette Sandholm, additional, Jensen, Poul Erik, additional, Nissen, Poul, additional, and Arleth, Lise, additional

Published
2017
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40. The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis

Author

Skov, Martin, Ruijs, Titia Q., Grønnebæk, Thomas S., Skals, Marianne, Riisager, Anders, Winther, Jeppe Blichfeldt, Dybdahl, Kamilla Løhde Tordrup, Findsen, Anders, Morgen, Jeanette J., Huus, Nete, Broch-Lips, Martin, Nielsen, Ole B., de Cuba, Catherine M.K.E., Heuberger, Jules A.A.C., de Kam, Marieke L., Tannemaat, Martijn, Verschuuren, Jan J. G. M., Knutsen, Lars J. S., Kelly, Nicholas M., Jensen, Klaus G., Arnold, William D., Burghes, Arthur H., Olesen, Claus, Bold, Jane, Petersen, Thomas K., Quiroz, Jorge A., Hutchison, John, Chin, Eva R., Groeneveld, Geert J., and Pedersen, Thomas H.

Abstract

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl−) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

Published
2024
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41. HiLiDeSystematic Approach to Membrane Protein Crystallization in Lipid and Detergent

Author

Gourdon, Pontus, Andersen, Jacob Lauwring, Hein, Kim Langmach, Bublitz, Maike, Pedersen, Bjørn Panyella, Liu, Xiang-Yu, Yatime, Laure, Nyblom, Maria, Nielsen, Thorbjørn Terndrup, Olesen, Claus, Møller, Jesper Vuust, Nissen, Poul, and Morth, Jens Preben

Abstract

To obtain the initial crystallization hit and the subsequent optimization remain the major bottlenecks in membrane protein structure determination. Here we describe an approach to achieve diffraction quality membrane protein crystals in high concentrations of lipid and detergent (HILIDE). Initial hits are achieved through a controlled variation of the membrane protein/lipid/detergent ratios, and optimized crystals are established by systematic screening with secondary detergents at concentrations that are adapted for the method. The approach is generally applicable for native and heterologously expressed membrane proteins, and it is compatible with any crystallization method, such as vapor diffusion and batch crystallization under oil. The method provides a user defined lipidic environment and is in itself not limited to lipids with particular properties, such as the lipid-phase crystallization methods.

Published
2024
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43. Den hvide Ridders død

Author

Olesen, Claus Rohden and Olesen, Claus Rohden

Abstract

Den hvide Ridders død

Published
2015

44. Structural studies of P-type ATPase-ligand complexes using an X-ray free-electron laser

Author

Bublitz, Maike, Nass, Karol, Drachmann, Nikolaj D., Markvardsen, Anders J., Gutmann, Matthias J., Barends, Thomas R. M., Mattle, Daniel, Shoeman, Robert L., Doak, R. Bruce, Boutet, Sebastien, Messerschmidt, Marc, Seibert, Marvin M., Williams, Garth J., Foucar, Lutz, Reinhard, Linda, Sitsel, Oleg, Gregersen, Jonas L., Clausen, Johannes D., Boesen, Thomas, Gotfryd, Kamil, Wang, Kai-Tuo, Olesen, Claus, Moller, Jesper V., Nissen, Poul, Schlichting, Ilme, Bublitz, Maike, Nass, Karol, Drachmann, Nikolaj D., Markvardsen, Anders J., Gutmann, Matthias J., Barends, Thomas R. M., Mattle, Daniel, Shoeman, Robert L., Doak, R. Bruce, Boutet, Sebastien, Messerschmidt, Marc, Seibert, Marvin M., Williams, Garth J., Foucar, Lutz, Reinhard, Linda, Sitsel, Oleg, Gregersen, Jonas L., Clausen, Johannes D., Boesen, Thomas, Gotfryd, Kamil, Wang, Kai-Tuo, Olesen, Claus, Moller, Jesper V., Nissen, Poul, and Schlichting, Ilme

Published
2015

48. Structural studies of P-type ATPase–ligand complexes using an X-ray free-electron laser

Author

Bublitz, Maike, primary, Nass, Karol, additional, Drachmann, Nikolaj D., additional, Markvardsen, Anders J., additional, Gutmann, Matthias J., additional, Barends, Thomas R. M., additional, Mattle, Daniel, additional, Shoeman, Robert L., additional, Doak, R. Bruce, additional, Boutet, Sébastien, additional, Messerschmidt, Marc, additional, Seibert, Marvin M., additional, Williams, Garth J., additional, Foucar, Lutz, additional, Reinhard, Linda, additional, Sitsel, Oleg, additional, Gregersen, Jonas L., additional, Clausen, Johannes D., additional, Boesen, Thomas, additional, Gotfryd, Kamil, additional, Wang, Kai-Tuo, additional, Olesen, Claus, additional, Møller, Jesper V., additional, Nissen, Poul, additional, and Schlichting, Ilme, additional

Published
2015
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