Search

Your search keyword '"Schulze, Jörg O."' showing total 27 results
Start Over Author "Schulze, Jörg O."
27 results on '"Schulze, Jörg O."'

2. Modulation of the substrate specificity of the kinase PDK1 by distinct conformations of the full-length protein

Author

Sacerdoti, Mariana, primary, Gross, Lissy Z. F., additional, Riley, Andrew M., additional, Zehnder, Karin, additional, Ghode, Abhijeet, additional, Klinke, Sebastián, additional, Anand, Ganesh Srinivasan, additional, Paris, Kristina, additional, Winkel, Angelika, additional, Herbrand, Amanda K., additional, Godage, H. Yasmin, additional, Cozier, Gyles E., additional, Süß, Evelyn, additional, Schulze, Jörg O., additional, Pastor-Flores, Daniel, additional, Bollini, Mariela, additional, Cappellari, María Victoria, additional, Svergun, Dmitri, additional, Gräwert, Melissa A., additional, Aramendia, Pedro F., additional, Leroux, Alejandro E., additional, Potter, Barry V. L., additional, Camacho, Carlos J., additional, and Biondi, Ricardo M., additional

Published
2023
Full Text
View/download PDF

4. Modulation of the substrate specificity of the kinase PDK1 by distinct conformations of the full-length protein

Author

Sacerdoti, Mariana, Gross, Lissy, Riley, Andrew M., Zehnder, Karin, Ghode, Abhijeet, Klinke, Sebastián, Anand, Ganesh Srinivasan, Paris, Kristina, Winkel, Angelika, Herbrand, Amanda K., Godage, H. Yasmin, Cozier, Gyles E., Süß, Evelyn, Schulze, Jörg O., Pastor-Flores, Daniel, Bollini, Mariela, Cappellari, María Victoria, Svergun, Dmitri, Gräwert, Melissa A., Aramendia, Pedro F., Leroux, Alejandro E., Potter, Barry V. L., Camacho, Carlos J., and Biondi, Ricardo M.

Subjects
ddc:500
Abstract

Science signaling 16(789), eadd3184 (2023). doi:10.1126/scisignal.add3184, The activation of at least 23 different mammalian kinases requires the phosphorylation of their hydrophobic motifs by the kinase PDK1. A linker connects the phosphoinositide-binding PH domain to the catalytic domain, which contains a docking site for substrates called the PIF pocket. Here, we used a chemical biology approach to show that PDK1 existed in equilibrium between at least three distinct conformations with differing substrate specificities. The inositol polyphosphate derivative HYG8 bound to the PH domain and disrupted PDK1 dimerization by stabilizing a monomeric conformation in which the PH domain associated with the catalytic domain and the PIF pocket was accessible. In the absence of lipids, HYG8 potently inhibited the phosphorylation of Akt (also termed PKB) but did not affect the intrinsic activity of PDK1 or the phosphorylation of SGK, which requires docking to the PIF pocket. In contrast, the small-molecule valsartan bound to the PIF pocket and stabilized a second distinct monomeric conformation. Our study reveals dynamic conformations of full-length PDK1 in which the location of the linker and the PH domain relative to the catalytic domain determines the selective phosphorylation of PDK1 substrates. The study further suggests new approaches for the design of drugs to selectively modulate signaling downstream of PDK1., Published by Assoc., Washington, DC [u.a.]

Published
2023

6. Camptothecin and its analog SN-38, the active metabolite of irinotecan, inhibit binding of the transcriptional regulator and oncoprotein FUBP1 to its DNA target sequence FUSE

Author

Hosseini, Sabrina Khageh, Kolterer, Stefanie, Steiner, Marlene, von Manstein, Viktoria, Gerlach, Katharina, Trojan, Jörg, Waidmann, Oliver, Zeuzem, Stefan, Schulze, Jörg O., Hahn, Steffen, Steinhilber, Dieter, Gatterdam, Volker, Tampé, Robert, Biondi, Ricardo M., Proschak, Ewgenij, and Zörnig, Martin

Published
2017
Full Text
View/download PDF

13. Camptothecin and its analog SN-38, the active metabolite of irinotecan, inhibit binding of the transcriptional regulator and oncoprotein FUBP1 to its DNA target sequence FUSE

Author

Khageh Hosseini, Sabrina, primary, Kolterer, Stefanie, additional, Steiner, Marlene, additional, von Manstein, Viktoria, additional, Gerlach, Katharina, additional, Trojan, Jörg, additional, Waidmann, Oliver, additional, Zeuzem, Stefan, additional, Schulze, Jörg O., additional, Hahn, Steffen, additional, Steinhilber, Dieter, additional, Gatterdam, Volker, additional, Tampé, Robert, additional, Biondi, Ricardo M., additional, Proschak, Ewgenij, additional, and Zörnig, Martin, additional

Published
2017
Full Text
View/download PDF

14. An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms

Author

Arencibia, Jose M., primary, Fröhner, Wolfgang, additional, Krupa, Magdalena, additional, Pastor-Flores, Daniel, additional, Merker, Piotr, additional, Oellerich, Thomas, additional, Neimanis, Sonja, additional, Schmithals, Christian, additional, Köberle, Verena, additional, Süß, Evelyn, additional, Zeuzem, Stefan, additional, Stark, Holger, additional, Piiper, Albrecht, additional, Odadzic, Dalibor, additional, Schulze, Jörg O., additional, and Biondi, Ricardo M., additional

Published
2017
Full Text
View/download PDF

17. Structural and functional characterization of human Iba proteins

Author

Schulze, Jörg O, Quedenau, Claudia, Roske, Yvette, Adam, Thomas, Schüler, Herwig, Behlke, Joachim, Turnbull, Andrew P, Sievert, Volker, Scheich, Christoph, Mueller, Uwe, Heinemann, Udo, Büssow, Konrad, and Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Subjects
Models, Molecular, Calcium-Binding Proteins, Microfilament Proteins, Molecular Sequence Data, Crystallography, X-Ray, Actins, DNA-Binding Proteins, Hela Cells, Humans, Calcium, Amino Acid Sequence, Shigella, Dimerization, Sequence Alignment
Abstract

Iba2 is a homolog of ionized calcium-binding adapter molecule 1 (Iba1), a 17-kDa protein that binds and cross-links filamentous actin (F-actin) and localizes to membrane ruffles and phagocytic cups. Here, we present the crystal structure of human Iba2 and its homodimerization properties, F-actin cross-linking activity, cellular localization and recruitment upon bacterial invasion in comparison with Iba1. The Iba2 structure comprises two central EF-hand motifs lacking bound Ca2+. Iba2 crystallized as a homodimer stabilized by a disulfide bridge and zinc ions. Analytical ultracentrifugation revealed a different mode of dimerization under reducing conditions that was independent of Ca2+. Furthermore, no binding of Ca2+ up to 0.1 mM was detected by equilibrium dialysis. Correspondingly, Iba EF-hand motifs lack residues essential for strong Ca2+ coordination. Sedimentation experiments and microscopy detected pronounced, indistinguishable F-actin binding and cross-linking activity of Iba1 and Iba2 with induction of F-actin bundles. Fluorescent Iba fusion proteins were expressed in HeLa cells and co-localized with F-actin. Iba1 was recruited into cellular projections to a larger extent than Iba2. Additionally, we studied Iba recruitment in a Shigella invasion model that induces cytoskeletal rearrangements. Both proteins were recruited into the bacterial invasion zone and Iba1 was again concentrated slightly higher in the cellular extensions.

Published
2008

18. PIF-Pocket as a Target for C. albicans Pkh Selective Inhibitors

Author

Pastor-Flores, Daniel, primary, Schulze, Jörg O., additional, Bahí, Anna, additional, Giacometti, Romina, additional, Ferrer-Dalmau, Jofre, additional, Passeron, Susana, additional, Engel, Matthias, additional, Süß, Evelyn, additional, Casamayor, Antonio, additional, and Biondi, Ricardo M., additional

Published
2013
Full Text
View/download PDF

19. Substrate-Selective Inhibition of Protein Kinase PDK1 by Small Compounds that Bind to the PIF-Pocket Allosteric Docking Site

Author

Busschots, Katrien, primary, Lopez-Garcia, Laura A., additional, Lammi, Carmen, additional, Stroba, Adriana, additional, Zeuzem, Stefan, additional, Piiper, Albrecht, additional, Alzari, Pedro M., additional, Neimanis, Sonja, additional, Arencibia, Jose M., additional, Engel, Matthias, additional, Schulze, Jörg O., additional, and Biondi, Ricardo M., additional

Published
2012
Full Text
View/download PDF

20. Allosteric regulation of protein kinase PKCζ by the N‐terminal C1 domain and small compounds to the PIF‐pocket

Author

Biondi, Ricardo M., primary, Schulze, Jörg O., additional, Fröhner, Wolfgang, additional, Zhang, Hua, additional, Weber, Nadja, additional, Navratil, Jeanette, additional, Amon, Sabine, additional, Hindie, Valerie, additional, Zeuzem, Stefan, additional, Jørgensen, Thomas J.D., additional, Alzari, Pedro M., additional, Neimanis, Sonja, additional, Engel, Matthias, additional, and Lopez-Garcia, Laura A., additional

Published
2012
Full Text
View/download PDF

21. Allosteric Regulation of Protein Kinase PKCζ by the N-Terminal C1 Domain and Small Compounds to the PIF-Pocket

Author

Lopez-Garcia, Laura A., primary, Schulze, Jörg O., additional, Fröhner, Wolfgang, additional, Zhang, Hua, additional, Süß, Evelyn, additional, Weber, Nadja, additional, Navratil, Jeanette, additional, Amon, Sabine, additional, Hindie, Valerie, additional, Zeuzem, Stefan, additional, Jørgensen, Thomas J.D., additional, Alzari, Pedro M., additional, Neimanis, Sonja, additional, Engel, Matthias, additional, and Biondi, Ricardo M., additional

Published
2011
Full Text
View/download PDF

22. Structure and allosteric effects of activating compounds on protein kinase PDK1

Author

Schulze, Jörg O., primary, Hindie, V., additional, Stroba, A., additional, Zhang, H., additional, Lopez-Garcia, L. A., additional, Idrissova, L., additional, Zeuzem, S., additional, Hirschberg, D., additional, Schaeffer, F., additional, Jørgensen, T. J., additional, Engel, M., additional, Alzari, P. M., additional, and Biondi, R. M., additional

Published
2010
Full Text
View/download PDF

26. PIF-Pocket as a Target for C. albicansPkh Selective Inhibitors

Author

Pastor-Flores, Daniel, Schulze, Jörg O., Bahí, Anna, Giacometti, Romina, Ferrer-Dalmau, Jofre, Passeron, Susana, Engel, Matthias, Süß, Evelyn, Casamayor, Antonio, and Biondi, Ricardo M.

Abstract

The phosphoinositide-dependent protein kinase 1, PDK1, is a master kinase that phosphorylates the activation loop of up to 23 AGC kinases. S. cerevisiaehas three PDK1 orthologues, Pkh1–3, which also phosphorylate AGC kinases (e.g., Ypk, Tpk, Pkc1, and Sch9). Pkh1 and 2 are redundant proteins involved in multiple essential cellular functions, including endocytosis and cell wall integrity. Based on similarities with the budding yeast, the Pkh of fungal infectious species was postulated as a novel target for antifungals. Here, we found that depletion of Pkh eventually induces oxidative stress and DNA double-strand breaks, leading to programmed cell death. This finding supports Pkh as an antifungal target since pharmacological inhibition of Pkh would lead to the death of yeast cells, the ultimate goal of antifungals. It was therefore of interest to further investigate the possibility to develop Pkh inhibitors with selectivity for Candida Pkh that would not inhibit the human ortholog. Here, we describe C. albicansPkh2 biochemically, structurally and by using chemical probes in comparison to human PDK1. We found that a regulatory site on the C. albicansPkh2 catalytic domain, the PIF-pocket, diverges from human PDK1. Indeed, we identified and characterized PS77, a new small allosteric inhibitor directed to the PIF-pocket, which has increased selectivity for C. albicansPkh2. Together, our results describe novel features of the biology of Pkh and chemical biology approaches that support the validation of Pkh as a drug target for selective antifungals.

Published
2013
Full Text
View/download PDF

27. 2-(3-Oxo-1,3-diphenylpropyl)malonic acids as potent allosteric ligands of the PIF pocket of phosphoinositide-dependent kinase-1: development and prodrug concept.

Author

Wilhelm A, Lopez-Garcia LA, Busschots K, Fröhner W, Maurer F, Boettcher S, Zhang H, Schulze JO, Biondi RM, and Engel M

Subjects
Allosteric Site, Binding Sites, DNA Helicases metabolism, Enzyme Activation, Humans, Immunoblotting, Malonates chemical synthesis, Models, Molecular, Molecular Structure, Muscle Cells metabolism, Prodrugs chemical synthesis, Protein Binding, Protein Kinase Inhibitors chemical synthesis, Protein Serine-Threonine Kinases metabolism, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Structure-Activity Relationship, DNA Helicases antagonists & inhibitors, Drug Design, Malonates chemistry, Malonates pharmacology, Muscle Cells drug effects, Prodrugs pharmacology, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors
Abstract

The protein kinase C-related kinase 2 (PRK2)-interacting fragment (PIF) pocket of phosphoinositide-dependent kinase-1 (PDK1) was proposed as a novel target site for allosteric modulators. In the present work, we describe the design, synthesis, and structure-activity relationship of a series of 2-(3-oxo-1,3-diphenylpropyl)malonic acids as potent allosteric activators binding to the PIF pocket. Some congeners displayed AC(50) values for PDK1 activation in the submicromolar range. The potency of the best compounds to stabilize PDK1 in a thermal stability shift assay was in the same order of magnitude as that of the PIF pocket binding peptide PIFtide, suggesting comparable binding affinities to the PIF pocket. The crystal structure of PDK1 in complex with compound 4h revealed that additional ionic interactions are mainly responsible for the increased potency compared to the monocarboxylate analogues. Notably, several compounds displayed high selectivity for PDK1. Employing a prodrug strategy, we were able to corroborate the novel mechanism of action in cells.

Published
2012
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results