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.

中文翻译：

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与正构和变构位点的双重结合增强了TRAP1靶向药物的抗癌活性。

分子伴侣TRAP1是Hsp90的线粒体旁系同源物，在许多癌细胞中过表达。TRAP1的正构ATP结合位点被认为是主要的抑制剂结合位点，但尚未研究TRAP1变构调节剂。在这里，我们生成并表征了Hsp90抑制剂PU-H71，它与线粒体递送载体三苯基phosph（TPP）结合在一起，并带有一个名为SMTIN-C10的C10碳间隔基，以实现与正构和变构位点的双重结合。除了通过PU-H71部分与ATP结合位点紧密结合外，SMTIN-C10还通过TPP部分与N末端域中的E115残基相互作用，随后诱导TRAP1发生结构转变为紧密堆积的封闭形式。