National Cancer Institute, Urologic Oncology Branch, Bldg 10/CRC, Room 1-5940, 9000 Rockville Pike, Bethesda, MD 20892, USA +1 301 496 5899 ; +1 301 402 0922 ;
Expert Opin Drug Discov. 2007 Oct;2(10):1403-14. doi: 10.1517/17460441.2.10.1403.
Heat-shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of many signaling proteins that are often activated, mutated or overexpressed in cancer cells and that underly cancer cell proliferation and survival. Hsp90 is a conformationally flexible protein that associates with a distinct set of cochaperones depending on ATP or ADP occupancy of an N-terminal binding pocket. Nucleotide exchange and ATP hydrolysis by Hsp90 itself, with the assistance of cochaperones, drive the Hsp90 chaperone machine to bind, chaperone and release client proteins. Cycling of the Hsp90 chaperone machine is critical to its function. Although ATP binding and hydrolysis have been convincingly implicated in regulating the Hsp90 cycle, growing evidence suggests that various post-translational modifications of Hsp90, including phosphorylation, acetylation and other modifications, provide an additional overlapping or parallel level of regulation. A more complete understanding of how these various protein modifications are regulated and interact with each other at the cellular level to modulate Hsp90 chaperone activity is critical to the design of novel approaches to inhibit this medically important molecular target.
热休克蛋白 90（Hsp90）是一种分子伴侣，对于许多信号蛋白的稳定性和功能至关重要，这些信号蛋白在癌细胞中经常被激活、突变或过度表达，并且是癌细胞增殖和存活的基础。Hsp90 是一种构象灵活的蛋白质，根据 N 端结合口袋中 ATP 或 ADP 的占据情况，与一组独特的共伴侣蛋白结合。Hsp90 本身的核苷酸交换和 ATP 水解，在共伴侣蛋白的协助下，驱动 Hsp90 伴侣机器结合、伴侣和释放客户蛋白。Hsp90 伴侣机器的循环对其功能至关重要。尽管 ATP 结合和水解已被令人信服地表明调节 Hsp90 循环，但越来越多的证据表明，Hsp90 的各种翻译后修饰，包括磷酸化、乙酰化和其他修饰，提供了额外的重叠或平行调节水平。更全面地了解这些不同的蛋白质修饰如何在细胞水平上相互调节以及相互作用，以调节 Hsp90 伴侣活性，对于设计抑制这一重要医学分子靶标的新方法至关重要。
