Understanding ligand-based modulation of the Hsp90 molecular chaperone dynamics at atomic resolution
Understanding ligand-based modulation of the Hsp90 molecular chaperone dynamics at atomic resolution
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DOI：
10.1073/pnas.0802879105
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发表时间：
2008-06-10
影响因子：
11.1
通讯作者：
Verkhivker, Gennady
中科院分区：
文献类型：
--
作者：
Colombo, Giorgio;Morra, Giulia;Verkhivker, Gennady
分子开关和基于配体的调制90 kDa的热休克蛋白（Hsp 90）分子伴侣活性可能最终促进构象偶联的ATP酶循环沿着激活和招聘的广泛的客户端蛋白。我们提出了一个原子分辨率分析热休克蛋白90 N-末端结构域（NTD）结合能景观模拟蛋白质动力学与一系列的结合伙伴。我们表明，分子伴侣的活性可能与（i）结合后的“活性位点盖子”的局部折叠-展开转换和构象转换以及（ii）结合伴侣的功能在潜在蛋白质动力学中的差异有关。这项研究表明，热休克蛋白90 NTD的结构可塑性可以利用分子伴侣机制来调节增强的结构刚性在ATP结合和增加的蛋白质的灵活性作为抑制剂结合的结果。本研究同意与实验结构数据，并提供了一个合理的分子模型，了解机制的调制分子伴侣的活动结合伙伴。
Molecular switching and ligand-based modulation of the 90-kDa heat-shock protein (Hsp90) chaperone activity may ultimately facilitate conformational coupling to the ATPase cycle along with activation and recruitment of the broad range of client proteins. We present an atomic resolution analysis of the Hsp90 N-terminal domain (NTD) binding energy landscape by simulating protein dynamics with a range of binding partners. We show that the activity of the molecular chaperone may be linked to (i) local folding-unfolding transitions and conformational switching of the "active site lid" upon binding and (it) differences in the underlying protein dynamics as a function of the binding partner. This study suggests that structural plasticity of the Hsp90 NTD can be exploited by the molecular chaperone machinery to modulate enhanced structural rigidity during ATP binding and increased protein flexibility as a consequence of the inhibitor binding. The present study agrees with the experimental structural data and provides a plausible molecular model for understanding mechanisms of modulation of molecular chaperone activities by binding partners.