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

PfHop 作为抗疟疾药物开发靶标的分子相互作用

• 批准号: 215044407
• 负责人: Professor Dr. Klaus Lingelbach (†)
• 金额: --
• 依托单位: Fachbereich 17: Biologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/215044407?language=en
• 关键词: Molecular; interactions; PfHop; target; anti

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 (Wegele et al., 2006). 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 (Dittmar and Pratt, 1997). In eukaryotes, the essential interaction between Hsp70 and Hsp90 is mediated by the Hsp70-Hsp90 Organising Protein, HOP (Nicolet and Craig, 1989). Both Hsp70 and Hsp90 possess C-terminally located EEVD motifs that interact with Hop via its tetratricopeptide repeat (TPR) domains, TPR1 and TPR2A motifs, respectively (Scheufler et al., 2000). It is most likely that the Hsp70-Hsp90 functional partnership in Plasmodium spp. facilitates the folding of key proteins in the parasite cell, particularly those involved in signal transduction. PfHsp90 is known to play an essential role in the survival of the parasite and the antibiotic geldanamycin is known to inhibit its function (Banumathy et al., 2003). In the previous funding period, we have studied PfHsp70-1, with a view to its possible usage as a drug target. Having fulfilled many of the targets we set for the initial funding period, in the next funding period, we wish to study the importance of PfHop for survival of the parasite. We suggest that, due to its highly important role in choreographing chaperone/chaperone interactions, PfHop and its interaction with other chaperones, may represent an ideal target for 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（Wegele等人，2006年）。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，以便使它们采用构象能力用于激素结合（Dittmar和Pratt，1997）。在真核生物中，Hsp 70和Hsp 90之间的基本相互作用是由Hsp 70-Hsp 90组织蛋白HOP介导的（尼科莱和克雷格，1989年）。Hsp 70和Hsp 90都具有位于C末端的EEVD基序，其分别通过其三肽重复（TPR）结构域，TPR 1和TPR 2A基序与Hop相互作用（Scheufler等人，2000年）。Hsp 70-Hsp 90在疟原虫中的功能伙伴关系最有可能是Hsp 70-Hsp 90。促进寄生虫细胞中关键蛋白的折叠，特别是那些参与信号转导的蛋白。已知PfHSP 90在寄生虫的存活中起重要作用，并且已知抗生素格尔德霉素抑制其功能（Banumathy等人，2003年）。在上一个资助期内，我们研究了PfHsp 70 -1，以探讨其作为药物靶点的可能性。在实现了我们为初始资助期设定的许多目标后，在下一个资助期，我们希望研究PfHop对寄生虫生存的重要性。我们认为，由于其高度重要的作用，在编排分子伴侣/分子伴侣的相互作用，PfHop和它与其他分子伴侣的相互作用，可能是一个理想的药物开发的目标。