利用核磁共振技术，通过Hsp90结构域鉴定N端和C端Hsp90抑制剂的结合区域。
Using NMR to identify binding regions for N and C-terminal Hsp90 inhibitors using Hsp90 domains.
作者信息
McConnell Jeanette R, Dyson H Jane, McAlpine Shelli R
机构信息
Work performed at School of Chemistry , University of New South Wales , Sydney , Australia . Email:
Work also performed at Scripps Research , 10550 North Torrey Pines Road , La Jolla , CA 92037 , USA . Email:
出版信息
RSC Med Chem. 2021 Feb 15;12(3):410-415. doi: 10.1039/d0md00387e. eCollection 2021 Mar 1.
We present the first NMR study of the interaction between heat shock protein 90 (Hsp90) and amino (N)-terminal inhibitors 17-AAG, and AUY922, and carboxy (C)-terminal modulators SM253, and LB51. We show that the two ATP mimics, 17-AAG and AUY922, bind deeply within the ATP binding pocket of the N-terminal domain, consistent with the crystal structures. In contrast, SM253, a C-terminal Hsp90 modulator, binds to the linker region between the N and middle domains. We also show that C-terminal inhibitor LB51 binds to the C-terminus with a more significant spectroscopic change than previously reported using NMR binding studies of C-terminal inhibitors novobiocin and silybin. These data provide key insights into how the allosteric inhibitor SM253 controls the C-terminal co-chaperones and confirms the binding domain of LB51.
我们展示了第一项关于热休克蛋白90（Hsp90）与氨基（N）末端抑制剂17-AAG、AUY922以及羧基（C）末端调节剂SM253和LB51之间相互作用的核磁共振（NMR）研究。我们发现，两种ATP模拟物17-AAG和AUY922，与N末端结构域的ATP结合口袋内部深处结合，这与晶体结构一致。相比之下，C末端Hsp90调节剂SM253，与N结构域和中间结构域之间的连接区域结合。我们还表明，C末端抑制剂LB51与C末端结合时，产生了比之前使用C末端抑制剂新生霉素和水飞蓟宾的NMR结合研究报告中更为显著的光谱变化。这些数据为变构抑制剂SM253如何控制C末端共伴侣提供了关键见解，并确定了LB51的结合结构域。
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