| Autor: |
Zehe M; University of Würzburg, Institute of Pharmacy and Food Chemistry, Am Hubland, DE-97074 Würzburg, Germany., Kehrein J; University of Würzburg, Institute of Pharmacy and Food Chemistry, Am Hubland, DE-97074 Würzburg, Germany., Schollmayer C; University of Würzburg, Institute of Pharmacy and Food Chemistry, Am Hubland, DE-97074 Würzburg, Germany., Plank C; University of Würzburg, Institute of Pharmacy and Food Chemistry, Am Hubland, DE-97074 Würzburg, Germany.; University of Würzburg, Department of Biochemistry and Cancer Therapy Research Center (CTRC), Theodor-Boveri-Institute, Am Hubland, DE-97074 Würzburg, Germany., Kovacs H; Bruker Switzerland AG, Industriestrasse 26, CH-8117 Fällanden, Switzerland., Merino Asumendi E; University of Würzburg, Institute of Pharmacy and Food Chemistry, Am Hubland, DE-97074 Würzburg, Germany., Holzgrabe U; University of Würzburg, Institute of Pharmacy and Food Chemistry, Am Hubland, DE-97074 Würzburg, Germany., Grimm C; University of Würzburg, Department of Biochemistry and Cancer Therapy Research Center (CTRC), Theodor-Boveri-Institute, Am Hubland, DE-97074 Würzburg, Germany., Sotriffer C; University of Würzburg, Institute of Pharmacy and Food Chemistry, Am Hubland, DE-97074 Würzburg, Germany. |
| Abstrakt: |
Heat shock protein 70 (Hsp70) isoforms are key players in the regulation of protein homeostasis and cell death pathways and are therefore attractive targets in cancer research. Developing nucleotide-competitive inhibitors or allosteric modulators, however, has turned out to be very challenging for this protein family, and no Hsp70-directed therapeutics have so far become available. As the field could profit from alternative starting points for inhibitor development, we present the results of a fragment-based screening approach on a two-domain Hsp70 construct using in-solution NMR methods, together with X-ray-crystallographic investigations and mixed-solvent molecular dynamics simulations. The screening protocol resulted in hits on both domains. In particular, fragment binding in a deeply buried pocket at the substrate-binding domain could be detected. The corresponding site is known to be important for communication between the nucleotide-binding and substrate-binding domains of Hsp70 proteins. The main fragment identified at this position also offers an interesting starting point for the development of a dual Hsp70/Hsp90 inhibitor. |
