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Suh, Pann-Ghill
BioSignal Network Lab (BSN)
Research Interests
  • Signal transduction, cancer, metabolism, phospholipase C

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Development of a Mitochondria-Targeted Hsp90 Inhibitor Based on the Crystal Structures of Human TRAP1

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Title
Development of a Mitochondria-Targeted Hsp90 Inhibitor Based on the Crystal Structures of Human TRAP1
Author
Lee, ChangwookPark, Hye-KyungJeong, HanbinLim, JaehwaLee, An-JungCheon, Keun YoungKim, Chul-SuThomas, Ajesh P.Bae, BoramKim, Nam DooKim, Seong HeonSuh, Pann-GhillRyu, Ja-HyoungKang, Byoung Heon
Issue Date
2015-04
Publisher
AMER CHEMICAL SOC
Citation
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.137, no.13, pp.4358 - 4367
Abstract
The mitochondrial pool of Hsp90 and its mitochondrial paralogue, TRAP1, suppresses cell death and reprograms energy metabolism in cancer cells; therefore, Hsp90 and TRAP1 have been suggested as target proteins for anticancer drug development. Here, we report that the actual target protein in cancer cell mitochondria is TRAP1, and current Hsp90 inhibitors cannot effectively inactivate TRAP1 because of their insufficient accumulation in the mitochondria. To develop mitochondrial TRAP1 inhibitors, we determined the crystal structures of human TRAP1 complexed with Hsp90 inhibitors. The isopropyl amine of the Hsp90 inhibitor PU-H71 was replaced with the mitochondria-targeting moiety triphenylphosphonium to produce SMTIN-P01. SMTIN-P01 showed a different mode of action from the nontargeted PU-H71, as well as much improved cytotoxicity to cancer cells. In addition, we determined the structure of a TRAP1-adenylyl-imidodiphosphate (AMP-PNP) complex. On the basis of comparative analysis of TRAP1 structures, we propose a molecular mechanism of ATP hydrolysis that is crucial for chaperone function. ⓒ 2015 American Chemical Society
URI
https://scholarworks.unist.ac.kr/handle/201301/11508
URL
http://pubs.acs.org/doi/abs/10.1021/ja511893n
DOI
10.1021/ja511893n
ISSN
0002-7863
Appears in Collections:
CHM_Journal Papers
BIO_Journal Papers
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