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.…
Author: | Sebastian Bothe, Petra Hänzelmann, Stephan Böhler, Josef Kehrein, Markus Zehe, Christoph Wiedemann, Ute A. Hellmich, Ruth Brenk, Hermann Schindelin, Christoph Sotriffer |
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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): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |