Molecular interactions of chaperones as a target for anti-malarial drug development

热休克蛋白70（Hsp 70）和Hsp 90是研究最多的分子伴侣，它们本身负责细胞中其他蛋白质的折叠。Hsp 70结合非天然蛋白质，而Hsp 90的底物通常为天然样形式。因此，需要Hsp 70和Hsp 90两者来折叠的蛋白质在折叠过程中从Hsp 70转移到Hsp 90。真核细胞Hsp 90参与酪氨酸激酶、类固醇激素受体等信号转导分子的构象调控。 例如，类固醇激素受体与Hsp 90缔合，以便使它们采用用于激素结合的构象能力。除了Hsp 70和Hsp 90之外，还有许多辅助分子伴侣和其他蛋白质相互作用物，它们对于分子伴侣系统的有效功能以及因此有效的蛋白质稳态是必不可少的。我们以前的特点是恶性疟原虫同源的热休克蛋白70-热休克蛋白90组织蛋白（PfHop），并分析其与寄生虫编码的伴侣蛋白的相互作用。在上一个资助期间，我们有兴趣了解PfHop和PfHsp 70 -1/PfHsp 90之间的相互作用，以阻止这种相互作用。此外，我们希望建立用于药物筛选的蛋白质：蛋白质相互作用测定。在此更新建议中，我们建议继续分析恶性疟原虫系统中的伴侣/辅助伴侣相互作用，现在包括另一种分子相互作用物PfHsp 70-z。此外，我们现在将使用我们以前建立的相互作用测定来筛选库中阻断这种可能的必要分子相互作用的化合物。

Heat shock protein 70 (Hsp70) and Hsp90 are some of the most studied molecular chaperones, proteins which themselves are responsible for the folding of other proteins in the cell. Hsp70 binds non-native proteins whilst substrates of Hsp90 are usually in native-like forms. Proteins that require both Hsp70 and Hsp90 to fold are thus transferred from Hsp70 to Hsp90 during the folding process. Eukaryotic Hsp90 participates in the conformational regulation of signal transduction molecules, such as tyrosine kinases and steroid hormone receptors. For example, steroid hormone receptors associate with Hsp90 in order for them to adopt conformational competence for hormone binding. In addition to Hsp70 and Hsp90, there are numerous co-chaperones and other protein interactors which are essential for the efficient functioning of the chaperone system and thus efficient protein homeostasis. We have previously characterised a P. falciparum homologue of the Hsp70-Hsp90 Organising Protein (PfHop) and analysed its interaction with parasite encoded chaperones. In the previous funding period we were interested in understanding the interaction between PfHop and PfHsp70-1/PfHsp90 with a view to blocking this interaction. Additionally, we wished to establish protein:protein interaction assays for use in drug-screening. In this renewal proposal we propose to continue our analysis of chaperone/co-chaperone interactions in the P. falciparum system, now including one further molecular interactor, PfHsp70-z. Additionally, we shall now use our previously established interaction assays to screen libraries for compounds which block this likely essential molecular interaction.