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Ryu, Ja-Hyoung
Supramolecular NanoMaterials Lab (SUN)
Research Interests
  • Supramolecular assembly, synthetic peptide assembly, cancer drug delivery

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Dual Binding to Orthosteric and Allosteric Sites Enhances the Anticancer Activity of a TRAP1-Targeting Drug

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Title
Dual Binding to Orthosteric and Allosteric Sites Enhances the Anticancer Activity of a TRAP1-Targeting Drug
Author
Hu, SungFerraro, MariarosariaThomas, Ajesh P.Chung, Jeong MinYoon, Nam GuSeol, Ji-HoonKim, SangpilKim, Han-UlAn, Mi YoungOk, HaewonJung, Hyun SukRyu, Ja-HyoungColombo, GiorgioKang, Byoung Heon
Issue Date
2020-03
Publisher
AMER CHEMICAL SOC
Citation
JOURNAL OF MEDICINAL CHEMISTRY, v.63, no.6, pp.2930 - 2940
Abstract
The molecular chaperone TRAP1 is the mitochondrial paralog of Hsp90 and is overexpressed in many cancer cells. The orthosteric ATP-binding site of TRAP1 has been considered the primary inhibitor binding location, but TRAP1 allosteric modulators have not yet been investigated. Here, we generated and characterized the Hsp90 inhibitor PU-H71, conjugated to the mitochondrial delivery vehicle triphenylphosphonium (TPP) with a C-10 carbon spacer, named SMTIN-C10, to enable dual binding to orthosteric and allosteric sites. In addition to tight binding with the ATP-binding site through the PU-H71 moiety, SMTIN-C10 interacts with the E115 residue in the N-terminal domain through the TPP moiety and subsequently induces structural transition of TRAP1 to a tightly packed closed form. The data indicate the existence of a druggable allosteric site neighboring the orthosteric ATP pocket that can be exploited to develop potent TRAP1 modulators.
URI
https://scholarworks.unist.ac.kr/handle/201301/32030
URL
https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01420
DOI
10.1021/acs.jmedchem.9b01420
ISSN
0022-2623
Appears in Collections:
CHM_Journal Papers
BIO_Journal Papers
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