Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, Tucson, Arizona 85721, United States.
J Med Chem. 2021 Jun 10;64(11):7060-7082. doi: 10.1021/acs.jmedchem.0c02091. Epub 2021 May 19.
Hsp70s are among the most highly conserved proteins in all of biology. Through an iterative binding and release of exposed hydrophobic residues on client proteins, Hsp70s can prevent aggregation and promote folding to the native state of their client proteins. The human proteome contains eight canonical Hsp70s. Because Hsp70s are relatively promiscuous they play a role in folding a large proportion of the proteome. Hsp70s are implicated in disease through their ability to regulate protein homeostasis. In recent years, researchers have attempted to develop selective inhibitors of Hsp70 isoforms to better understand the role of individual isoforms in biology and as potential therapeutics. Selective inhibitors have come from rational design, forced localization, and serendipity, but the development of completely selective inhibitors remains elusive. In the present review, we discuss the Hsp70 structure and function, the known Hsp70 client proteins, the role of Hsp70s in disease, and current efforts to discover Hsp70 modulators.
热休克蛋白 70 家族是所有生物中高度保守的蛋白质之一。通过反复结合和释放客户蛋白上暴露的疏水性残基，热休克蛋白 70 家族可以防止聚集并促进客户蛋白折叠到其天然状态。人类蛋白质组包含 8 种典型的热休克蛋白 70 家族。由于热休克蛋白 70 家族相对混杂，它们在折叠蛋白质组的很大一部分中发挥作用。热休克蛋白 70 家族通过调节蛋白质稳态的能力而与疾病有关。近年来，研究人员试图开发热休克蛋白 70 家族亚型的选择性抑制剂，以更好地了解各个亚型在生物学中的作用以及作为潜在治疗药物的作用。选择性抑制剂来自合理设计、强制定位和偶然发现，但完全选择性抑制剂的开发仍然难以捉摸。在本综述中，我们讨论了热休克蛋白 70 家族的结构和功能、已知的热休克蛋白 70 家族客户蛋白、热休克蛋白 70 家族在疾病中的作用以及发现热休克蛋白 70 家族调节剂的当前努力。
