The Noncompetitive Effect of Gambogic Acid Displaces Fluorescence-Labeled ATP but Requires ATP for Binding to Hsp90/HtpG

authored by

Qing Yue, Frank Stahl, Oliver Plettenburg, Andreas Kirschning, Athanasia Warnecke, Carsten Zeilinger

Abstract

The heat shock protein 90 (Hsp90) family plays a critical role in maintaining the homeostasis of the intracellular environment for human and prokaryotic cells. Hsp90 orthologues were identified as important target proteins for cancer and plant disease therapies. It was shown that gambogic acid (GBA) has the potential to inhibit human Hsp90. However, it is unknown whether it is also able to act on the bacterial high-temperature protein (HtpG) analogue. In this work, we screened GBA and nine other novel potential Hsp90 inhibitors using a miniaturized high-throughput protein microarray-based assay and found that GBA shows an inhibitory effect on different Hsp90s after dissimilarity analysis of the protein sequence alignment. The dissociation constant of GBA and HtpG Xanthomonas (XcHtpG) computed from microscale thermophoresis is 682.2 ± 408 μM in the presence of ATP, which is indispensable for the binding of GBA to XcHtpG. Our results demonstrate that GBA is a promising Hsp90/HtpG inhibitor. The work further demonstrates that our assay concept has great potential for finding new potent Hsp/HtpG inhibitors.

Organisation(s)

Institute of Technical Chemistry
Centre of Biomolecular Drug Research (BMWZ)
Institute of Organic Chemistry
Institute of Cell Biology and Biophysics

External Organisation(s)

Hannover Medical School (MHH)
Helmholtz Zentrum München - German Research Center for Environmental Health

Type

Article

Journal

Biochemistry

Volume

57

Pages

2601-2605

No. of pages

5

ISSN

0006-2960

Publication date

08.05.2018

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Biochemistry

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1021/acs.biochem.8b00155 (Access: Closed)