TY  - JOUR
A1  - Bothe, Sebastian
A1  - Hänzelmann, Petra
A1  - Böhler, Stephan
A1  - Kehrein, Josef
A1  - Zehe, Markus
A1  - Wiedemann, Christoph
A1  - Hellmich, Ute A.
A1  - Brenk, Ruth
A1  - Schindelin, Hermann
A1  - Sotriffer, Christoph
T1  - Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97
T2  - Communications Chemistry
N2  - 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.
KW  - fragment screening
KW  - AAA+ ATPase p97
KW  - biosensor
Y1  - 2022
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/30082
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-300821
VL  - 5
IS  - 1
ER  -