@article{BotheHaenzelmannBoehleretal.2022,
  author    = {Bothe, Sebastian and H{\"a}nzelmann, Petra and B{\"o}hler, Stephan and Kehrein, Josef and Zehe, Markus and Wiedemann, Christoph and Hellmich, Ute A. and Brenk, Ruth and Schindelin, Hermann and Sotriffer, Christoph},
  title     = {Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97},
  series = {Communications Chemistry},
  volume    = {5},
  journal   = {Communications Chemistry},
  number    = {1},
  doi       = {10.1038/s42004-022-00782-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300821},
  year      = {2022},
  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.},
  language  = {en}
}