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首页> 外文期刊>Chemistry: A European journal >Activation of Hsp90 Enzymatic Activity and Conformational Dynamics through Rationally Designed Allosteric Ligands
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Activation of Hsp90 Enzymatic Activity and Conformational Dynamics through Rationally Designed Allosteric Ligands

机译：通过合理设计的变构配体激活Hsp90酶活性和构象动力学。

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摘要

Hsp90 is a molecular chaperone of pivotal importance for multiple cell pathways. ATP-regulated internal dynamics are critical for its function and current pharmacological approaches block the chaperone with ATP-competitive inhibitors. Herein, a general approach to perturb Hsp90 through design of new allosteric ligands aimed at modulating its functional dynamics is proposed. Based on the characterization of a first set of 2-phenylbenzofurans showing stimulatory effects on Hsp90 ATPase and conformational dynamics, new ligands were developed that activate Hsp90 by targeting an allosteric site, located 65 angstrom from the active site. Specifically, analysis of protein responses to first-generation activators was exploited to guide the design of novel derivatives with improved ability to stimulate ATP hydrolysis. The molecules' effects on Hsp90 enzymatic, conformational, co-chaperone and client-binding properties were characterized through biochemical, biophysical and cellular approaches. These designed probes act as allosteric activators of the chaperone and affect the viability of cancer cell lines for which proper functioning of Hsp90 is necessary.
机译：Hsp90是对多种细胞途径至关重要的分子伴侣。 ATP调节的内部动力学对其功能至关重要，当前的药理学方法用ATP竞争性抑制剂来阻断分子伴侣。在此，提出了一种通过设计新的变构配体来调节Hsp90的通用方法，旨在调节其功能动力学。基于第一组2-苯基苯并呋喃对Hsp90 ATPase的刺激作用和构象动力学的表征，开发了新的配体，该配体通过靶向一个位于活性位点65埃的变构位点来激活Hsp90。具体而言，利用对第一代活化剂的蛋白质反应的分析来指导具有提高的刺激ATP水解能力的新型衍生物的设计。通过生化，生物物理和细胞方法表征了分子对Hsp90酶，构象，伴侣蛋白和客户结合特性的影响。这些设计的探针充当伴侣的变构激活剂，并影响癌细胞系的生存能力，为此，Hsp90的正常功能是必需的。

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