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Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97

Please always quote using this URN: urn:nbn:de:bvb:20-opus-300821
  • 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 biolayerBiosensor 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.show moreshow less

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Metadaten
Author: Sebastian Bothe, Petra Hänzelmann, Stephan Böhler, Josef Kehrein, Markus Zehe, Christoph Wiedemann, Ute A. Hellmich, Ruth Brenk, Hermann Schindelin, Christoph Sotriffer
URN:urn:nbn:de:bvb:20-opus-300821
Document Type:Journal article
Faculties:Fakultät für Biologie / Rudolf-Virchow-Zentrum
Fakultät für Chemie und Pharmazie / Institut für Pharmazie und Lebensmittelchemie
Language:English
Parent Title (English):Communications Chemistry
Year of Completion:2022
Volume:5
Issue:1
Article Number:169
Source:Communications Chemistry 2022, 5(1):169. DOI: 10.1038/s42004-022-00782-5
DOI:https://doi.org/10.1038/s42004-022-00782-5
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 615 Pharmakologie, Therapeutik
Tag:AAA+ ATPase p97; biosensor; fragment screening
Release Date:2023/02/24
Collections:Open-Access-Publikationsfonds / Förderzeitraum 2022
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International