Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
Istituto di Chimica del Riconoscimento Molecolare (ICRM), Consiglio Nazionale delle Ricerche (CNR), Milan 20131, Italy.
J Med Chem. 2020 Mar 26;63(6):2930-2940. doi: 10.1021/acs.jmedchem.9b01420. Epub 2020 Mar 2.
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 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.
分子伴侣 TRAP1 是 Hsp90 的线粒体同系物，在许多癌细胞中过度表达。TRAP1 的正位 ATP 结合位点被认为是主要的抑制剂结合位置，但 TRAP1 的别构调节剂尚未被研究过。在这里，我们生成并表征了 Hsp90 抑制剂 PU-H71，它与线粒体递药载体三苯基膦（TPP）通过 C 碳间隔物连接，命名为 SMTIN-C10，以实现对正位和别位的双重结合。除了通过 PU-H71 部分与 ATP 结合位点紧密结合外，SMTIN-C10 通过 TPP 部分与 N 端结构域中的 E115 残基相互作用，随后诱导 TRAP1 发生结构转变，形成紧密堆积的封闭形式。这些数据表明存在一个紧邻正位 ATP 口袋的可成药的别构位点，可用于开发有效的 TRAP1 调节剂。
