Modulating protein-protein interaction networks in protein homeostasis.
Modulating protein-protein interaction networks in protein homeostasis.
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DOI：
10.1016/j.cbpa.2019.02.012
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发表时间：
2019-06
影响因子：
7.8
通讯作者：
Mengqi Zhong;Gregory M Lee;E. Sijbesma;C. Ottmann;M. Arkin
中科院分区：
文献类型：
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作者：
Mengqi Zhong;Gregory M Lee;E. Sijbesma;C. Ottmann;M. Arkin
蛋白质-蛋白质相互作用（PPI）发生在复杂的网络中。这些网络高度依赖于细胞环境，并且可以在癌症和病毒感染等疾病状态中广泛改变。近年来，在开发以正构（在界面处）或变构为靶点的个体PPI抑制剂方面取得了重大进展。这些分子现在可以用作剖析PPI网络的工具。在这里，我们回顾了最近的例子，强调使用小分子和工程蛋白质探针PPI内的复杂网络，调节蛋白质稳态。研究人员已经发现了多种机制来调节参与宿主/病毒相互作用的PPI，去泛素化酶，ATP酶p97/VCP和HSP 70伴侣。然而，很少有研究评估这种调制器对目标网络的影响，或比较不同调制策略的生物学意义。这些研究将对下一代疗法产生重要影响。
Protein–protein interactions (PPIs) occur in complex networks. These networks are highly dependent on cellular context and can be extensively altered in disease states such as cancer and viral infection. In recent years, there has been significant progress in developing inhibitors that targetindividualPPIs either orthosterically (at the interface) or allosterically. These molecules can now be used as tools to dissect PPInetworks. Here, we review recent examples that highlight the use of small molecules and engineered proteins to probe PPIs within the complex networks that regulate protein homeostasis. Researchers have discovered multiple mechanisms to modulate PPIs involved in host/viral interactions, deubiquitinases, the ATPase p97/VCP, and HSP70 chaperones. However, few studies have evaluated the effect of such modulators on the target’s network or have compared the biological implications of different modulation strategies. Such studies will have an important impact on next generation therapeutics.