Pan-HSP90 ligand binding reveals isoform-specific differences in plasticity and water networks.
Pan-HSP90 ligand binding reveals isoform-specific differences in plasticity and water networks.
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DOI：
10.1002/pro.4629
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发表时间：
2023-05
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影响因子：
--
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中科院分区：
文献类型：
--
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热休克蛋白90（HSP 90）的亚型折叠癌蛋白，促进癌症的所有10个标志。然而，它作为治疗靶点的承诺仍未实现，因为仍然没有FDA批准的靶向疾病中的HSP 90的药物。阻碍进展的原因之一是泛HSP 90抑制引起的副作用。由于高序列和结构相似性，四种同种型的选择性靶向是具有挑战性的。令人惊讶的是，虽然数十年的药物发现工作已经产生了近400种人类HSP 90结构，但迄今为止，还没有一种配体在所有四种人类亚型中进行结构表征，这可以揭示结构差异以实现选择性。为了更好地了解与配体结合和设计相关的HSP 90景观，我们采取了三管齐下的方法。首先，我们解决了与所有四种人类同种型结合的单个配体的第一组完整结构。这使得能够系统地比较侧链和水网络如何响应异构体之间的配体结合。其次，我们将我们的分析扩展到公开可用的，具有不同配体化学的不完整异构体-配体系列。这突出了蛋白质和水流动性的一般趋势，其在同种型之间不同并影响配体结合。第三，我们进一步探索了热休克蛋白90 α构象景观，以容纳含有热休克蛋白90抑制剂共有的嘌呤支架的同源系列。这揭示了微小的配体修饰如何翻转配体姿势并扰乱水和蛋白质构象。总之，这项工作说明了一个系统的方法如何可以揭示新的光在一个“老”的目标，并揭示隐藏的同种型特异性的住宿的同类配体，可以利用配体的发现和设计。PDB代码：7 ULJ、7 ULK和7 ULK;
Isoforms of heat shock protein 90 (HSP90) fold oncoproteins that facilitate all 10 hallmarks of cancer. However, its promise as a therapeutic target remains unfulfilled as there is still no FDA‐approved drug targeting HSP90 in disease. Among the reasons hindering progress are side effects caused by pan‐HSP90 inhibition. Selective targeting of the four isoforms is challenging due to high sequence and structural similarity. Surprisingly, while decades of drug discovery efforts have produced almost 400 human HSP90 structures, no single ligand has been structurally characterized across all four human isoforms to date, which could reveal structural differences to achieve selectivity. To better understand the HSP90 landscape relevant for ligand binding and design we take a three‐pronged approach. First, we solved the first complete set of structures of a single ligand bound to all four human isoforms. This enabled a systematic comparison of how side‐chains and water networks respond to ligand binding across isoforms. Second, we expanded our analysis to publicly available, incomplete isoform‐ligand series with distinct ligand chemistry. This highlighted general trends of protein and water mobility that differ among isoforms and impact ligand binding. Third, we further probed the Hsp90α conformational landscape for accommodating a congeneric series containing the purine scaffold common to HSP90 inhibitors. This revealed how minor ligand modifications flip ligand poses and perturb water and protein conformations. Taken together, this work illustrates how a systematic approach can shed new light on an “old” target and reveal hidden isoform‐specific accommodations of congeneric ligands that may be exploited in ligand discovery and design. PDB Code(s): 7ULJ, 7ULL and 7ULK;
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DOI：
10.1002/chem.201703398
发表时间：
2017-11-07
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
--
作者：
Crowley VM;Huard DJE;Lieberman RL;Blagg BSJ
通讯作者：
Blagg BSJ
DOI：
10.1073/pnas.1703287114
发表时间：
2017-08-15
影响因子：
11.1
作者：
Balius, Trent E.;Fischer, Marcus;Shoichet, Brian K.
通讯作者：
Shoichet, Brian K.
影响因子：
2.7
作者：
Ernst, Justin T.;Liu, Michael;Stamos, Dean
通讯作者：
Stamos, Dean
影响因子：
8.4
作者：
Bradford SYC;El Khoury L;Ge Y;Osato M;Mobley DL;Fischer M
通讯作者：
Fischer M
影响因子：
5.6
作者：
Immormino, Robert M.;Metzger, Louis E.;Reardon, Patrick N.;Dollins, D. Eric;Blagg, Brian S. J.;Gewirth, Daniel T.
通讯作者：
Gewirth, Daniel T.