Different poses for ligand and chaperone in inhibitor-bound Hsp90 and GRP94: implications for paralog-specific drug design.
Different poses for ligand and chaperone in inhibitor-bound Hsp90 and GRP94: implications for paralog-specific drug design.
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DOI：
10.1016/j.jmb.2009.03.071
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发表时间：
2009-05-22
影响因子：
5.6
通讯作者：
Gewirth, Daniel T.
中科院分区：
文献类型：
--
作者：
Immormino, Robert M.;Metzger, Louis E.;Reardon, Patrick N.;Dollins, D. Eric;Blagg, Brian S. J.;Gewirth, Daniel T.
HSP90分子伴侣含有一个N-末端的ATP结合位点，它是竞争性抑制剂的有效靶点。尽管有各种各样的抑制剂，但到目前为止，还没有一种抑制剂被设计成仅与四种哺乳动物HSP90同源基因中的一种结合，这四种同源基因分别是细胞质Hsp90α和β、ER GRP94和线粒体Trap-1。鉴于每个HSP90类似蛋白负责伴随一组不同的客户蛋白，特定靶向一个HSP90平行蛋白可能会导致更高的疗效和治疗控制。特定的抑制剂也可能有助于阐明每个HSP90类似蛋白的生化作用。在这里，我们并排比较了酵母HSP90和哺乳动物GRP94的结构，它们与PAN-HSP90抑制剂格尔达那霉素和雷达胺结合。这些结构揭示了Hsp90和GRP94构象对格尔达霉素结合的反应中的平行对数特异性差异。我们还报道了当格尔达霉素-自由基嵌合体雷达胺与两个对数结合时，其姿势和不同的结合亲和力发生了显著变化，这可能会在设计对数特异的抑制剂时被利用。
Hsp90 chaperones contain an N-terminal ATP binding site that has been effectively targeted by competitive inhibitors. Despite the myriad of inhibitors, none to date have been designed to bind specifically to just one of the four mammalian hsp90 paralogs, which are cytoplasmic Hsp90α and β, ER GRP94, and mitochondrial Trap-1. Given that each of the hsp90 paralogs is responsible for chaperoning a distinct set of client proteins, specific targeting of one hsp90 paralog may result in higher efficacy and therapeutic control. Specific inhibitors may also help elucidate the biochemical roles of each hsp90 paralog. Here we present side by side comparisons of the structures of yeast Hsp90 and mammalian GRP94, bound to the pan-hsp90 inhibitors Geldanamycin and Radamide. These structures reveal paralog specific differences in the Hsp90 and GRP94 conformations in response to Geldanamycin binding. We also report significant variation in the pose and disparate binding affinities for the Geldanamycin-Radicicol chimera Radamide when bound to the two paralogs, which may be exploited in the design of paralog-specific inhibitors.
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