Li Xiaokai, Shao Hao, Taylor Isabelle R, Gestwicki Jason E
University of California at San Francisco, Department of Pharmaceutical Chemistry, 675 Nelson Rising Lane, Room 311, San Francisco, CA 94038, USA.
Curr Top Med Chem. 2016;16(25):2729-40. doi: 10.2174/1568026616666160413140911.
Heat shock protein 70 (Hsp70) is a molecular chaperone that plays critical roles in protein homeostasis. Hsp70's chaperone activity is coordinated by intra-molecular interactions between its two domains, as well as inter-molecular interactions between Hsp70 and its co-chaperones. Each of these contacts represents a potential opportunity for the development of chemical inhibitors. To illustrate this concept, we review three classes of recently identified molecules that bind distinct pockets on Hsp70. Although all three compounds share the ability to interrupt core biochemical functions of Hsp70, they stabilize different conformers. Accordingly, each compound appears to interrupt a specific subset of inter- and intra-molecular interactions. Thus, an accurate definition of an Hsp70 inhibitor may require a particularly detailed understanding of the molecule's binding site and its effects on protein-protein interactions.
热休克蛋白70（Hsp70）是一种分子伴侣，在蛋白质稳态中发挥关键作用。Hsp70的伴侣活性由其两个结构域之间的分子内相互作用以及Hsp70与其共伴侣之间的分子间相互作用协调。这些相互作用中的每一个都代表了开发化学抑制剂的潜在机会。为了说明这一概念，我们回顾了最近鉴定出的三类与Hsp70上不同口袋结合的分子。尽管所有这三种化合物都具有中断Hsp70核心生化功能的能力，但它们稳定不同的构象。因此，每种化合物似乎都中断了分子间和分子内相互作用的特定子集。因此，对Hsp70抑制剂的准确定义可能需要对该分子的结合位点及其对蛋白质-蛋白质相互作用的影响有特别详细的了解。
