Sung's paper was published in J. Med. Chem.
Post date: Feb 19, 2020 1:57:42 PM
Sung Hu, Mariarosaria Ferraro, Ajesh P. Thomas, Jeong Min Chung, Nam Gu Yoon, Ji-Hoon Seol, Sangpil Kim, Han-ul Kim, Mi Young An, Haewon Ok, Hyun Suk Jung, Ja-Hyoung Ryu, Giorgio Colombo, Byoung Heon Kang
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 C10 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