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An atomistic view of Hsp70 allosteric crosstalk: from the nucleotide to the substrate binding domain and back.
Scientific Reports ( IF 3.8 ) Pub Date : 2016-Mar-30 , DOI: 10.1038/srep23474
Federica Chiappori , Ivan Merelli , Luciano Milanesi , Giorgio Colombo , Giulia Morra

The Hsp70 is an allosterically regulated family of molecular chaperones. They consist of two structural domains, NBD and SBD, connected by a flexible linker. ATP hydrolysis at the NBD modulates substrate recognition at the SBD, while peptide binding at the SBD enhances ATP hydrolysis. In this study we apply Molecular Dynamics (MD) to elucidate the molecular determinants underlying the allosteric communication from the NBD to the SBD and back. We observe that local structural and dynamical modulation can be coupled to large-scale rearrangements, and that different combinations of ligands at NBD and SBD differently affect the SBD domain mobility. Substituting ADP with ATP in the NBD induces specific structural changes involving the linker and the two NBD lobes. Also, a SBD-bound peptide drives the linker docking by increasing the local dynamical coordination of its C-terminal end: a partially docked DnaK structure is achieved by combining ATP in the NBD and peptide in the SBD. We propose that the MD-based analysis of the inter domain dynamics and structure modulation could be used as a tool to computationally predict the allosteric behaviour and functional response of Hsp70 upon introducing mutations or binding small molecules, with potential applications for drug discovery.

中文翻译:

Hsp70变构串扰的原子观:从核苷酸到底物结合结构域再返回。

Hsp70是分子伴侣的变构调控家族。它们由两个结构域NBD和SBD组成,它们通过一个灵活的连接子连接。NBD处的ATP水解可调节SBD处的底物识别,而SBD处的肽结合可增强ATP水解。在这项研究中,我们应用分子动力学(MD)阐明了从NBD到SBD以及返回的变构通讯基础的分子决定因素。我们观察到局部结构和动态调制可以耦合到大规模的重排,并且在NBD和SBD配体的不同组合会不同地影响SBD域的迁移率。在NBD中用ATP取代ADP会引起涉及接头和两个NBD裂片的特定结构变化。还,SBD结合的肽通过增加其C末端的局部动力学配位来驱动接头对接:通过结合NBD中的ATP和SBD中的肽,可以实现部分对接的DnaK结构。我们建议基于MD的域间动力学和结构调节的分析可以用作一种工具,用于在引入突变或结合小分子后预测Hsp70的变构行为和功能响应,并可能用于药物发现。
更新日期:2016-04-01
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