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首页> 外文期刊>Scientific reports. >Modulation of Human Hsp90α Conformational Dynamics by Allosteric Ligand Interaction at the C-Terminal Domain
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Modulation of Human Hsp90α Conformational Dynamics by Allosteric Ligand Interaction at the C-Terminal Domain

机译：C末端域的变构配体相互作用对人类Hsp90α构象动力学的调控。

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Recent years have seen heat shock protein 90?kDa (Hsp90) attract significant interest as a viable drug target, particularly for cancer. To date, designed inhibitors that target the ATPase domain demonstrate potent anti-proliferative effects, but have failed clinical trials due to high levels of associated toxicity. To circumvent this, the focus has shifted away from the ATPase domain. One option involves modulation of the protein through allosteric activation/inhibition. Here, we propose a novel approach: we use previously obtained information via residue perturbation scanning coupled with dynamic residue network analysis to identify allosteric drug targeting sites for inhibitor docking. We probe the open conformation of human Hsp90α for druggable sites that overlap with these allosteric control elements, and identify three putative natural compound allosteric modulators: Cephalostatin 17, 20(29)-Lupene-3β-isoferulate and 3′-Bromorubrolide F. We assess the allosteric potential of these ligands by examining their effect on the conformational dynamics of the protein. We find evidence for the selective allosteric activation and inhibition of Hsp90’s conformational transition toward the closed state in response to ligand binding and shed valuable insight to further the understanding of allosteric drug design and Hsp90’s complex allosteric mechanism of action.
机译：近年来，热休克蛋白90？kDa（Hsp90）作为可行的药物靶标引起了人们的极大兴趣，尤其是对于癌症。迄今为止，设计针对ATPase结构域的抑制剂显示出有效的抗增殖作用，但由于高水平的相关毒性而使临床试验失败。为了避免这种情况，重点从ATPase结构域转移了出去。一种选择涉及通过变构激活/抑制来调节蛋白质。在这里，我们提出了一种新颖的方法：我们通过残基扰动扫描结合动态残基网络分析，使用先前获得的信息来识别用于抑制剂对接的变构药物靶向位点。我们探究人类Hsp90α的开放构象，寻找与这些变构控制元件重叠的可药用位点，并鉴定出三种推定的天然化合物变构调节剂：头孢他汀17、20（29）-L-3β-异铁酸酯和3'-溴柔比星F。我们评估了通过检查它们对蛋白质构象动力学的影响，了解这些配体的变构潜力。我们发现了对配体结合有选择性的变构激活和抑制Hsp90向闭合状态构象转变的证据，并为进一步理解变构药物设计和Hsp90复杂的变构作用机理提供了宝贵的见解。

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