dc.contributor.author | Bothe, Sebastian | |
dc.contributor.author | Hänzelmann, Petra | |
dc.contributor.author | Böhler, Stephan | |
dc.contributor.author | Kehrein, Josef | |
dc.contributor.author | Zehe, Markus | |
dc.contributor.author | Wiedemann, Christoph | |
dc.contributor.author | Hellmich, Ute A. | |
dc.contributor.author | Brenk, Ruth | |
dc.contributor.author | Schindelin, Hermann | |
dc.contributor.author | Sotriffer, Christoph | |
dc.date.accessioned | 2023-03-13T09:45:44Z | |
dc.date.available | 2023-03-13T09:45:44Z | |
dc.date.created | 2022-12-16T17:01:10Z | |
dc.date.issued | 2022 | |
dc.identifier.issn | 2399-3669 | |
dc.identifier.uri | https://hdl.handle.net/11250/3057892 | |
dc.description.abstract | Biosensor techniques have become increasingly important for fragment-based drug discovery during the last years. The AAA+ ATPase p97 is an essential protein with key roles in protein homeostasis and a possible target for cancer chemotherapy. Currently available p97 inhibitors address its ATPase activity and globally impair p97-mediated processes. In contrast, inhibition of cofactor binding to the N-domain by a protein-protein-interaction inhibitor would enable the selective targeting of specific p97 functions. Here, we describe a biolayer interferometry-based fragment screen targeting the N-domain of p97 and demonstrate that a region known as SHP-motif binding site can be targeted with small molecules. Guided by molecular dynamics simulations, the binding sites of selected screening hits were postulated and experimentally validated using protein- and ligand-based NMR techniques, as well as X-ray crystallography, ultimately resulting in the first structure of a small molecule in complex with the N-domain of p97. The identified fragments provide insights into how this region could be targeted and present first chemical starting points for the development of a protein-protein interaction inhibitor preventing the binding of selected cofactors to p97. | en_US |
dc.language.iso | eng | en_US |
dc.publisher | Nature | en_US |
dc.rights | Navngivelse 4.0 Internasjonal | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/deed.no | * |
dc.title | Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97 | en_US |
dc.type | Journal article | en_US |
dc.type | Peer reviewed | en_US |
dc.description.version | publishedVersion | en_US |
dc.rights.holder | Copyright 2022 The Author(s) | en_US |
dc.source.articlenumber | 169 | en_US |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 1 | |
dc.identifier.doi | 10.1038/s42004-022-00782-5 | |
dc.identifier.cristin | 2094598 | |
dc.source.journal | Communications chemistry | en_US |
dc.identifier.citation | Communications chemistry. 2022, 5 (1), 169. | en_US |
dc.source.volume | 5 | en_US |
dc.source.issue | 1 | en_US |