Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; email:
Annu Rev Pharmacol Toxicol. 2016;56:191-209. doi: 10.1146/annurev-pharmtox-010814-124727.
The 26S proteasome is a 2.5-MDa complex, and it operates at the executive end of the ubiquitin-proteasome pathway. It is a proven target for therapeutic agents for the treatment of some cancers and autoimmune diseases, and moreover, it has potential as a target of antibacterial agents. Most inhibitors, including all molecules approved for clinical use, target the 20S proteolytic core complex; its structure was determined two decades ago. Hitherto, efforts to develop inhibitors targeting the 19S regulatory particle subunits have been less successful. This is, in part, because the molecular architecture of this subcomplex has been, until recently, poorly understood, and high-resolution structures have been available only for a few subunits. In this review, we describe, from a structural perspective, the development of inhibitory molecules that target both the 20S and 19S subunits of the proteasome. We highlight the recent progress achieved in structure-based drug-discovery approaches, and we discuss the prospects for further improvement.
26S 蛋白酶体是一个 2.5MDa 的复合物，它在泛素蛋白酶体途径的执行末端起作用。它是治疗某些癌症和自身免疫性疾病的治疗药物的既定靶点，此外，它还有可能成为抗菌药物的靶点。大多数抑制剂，包括所有已批准用于临床使用的分子，都针对 20S 蛋白酶核心复合物；其结构在二十年前就已经确定。迄今为止，针对 19S 调节颗粒亚基开发抑制剂的努力不太成功。部分原因是，直到最近，这个亚复合物的分子结构才得到很好的理解，而且只有少数亚基有高分辨率结构。在这篇综述中，我们从结构的角度描述了靶向蛋白酶体 20S 和 19S 亚基的抑制分子的发展。我们强调了基于结构的药物发现方法方面的最新进展，并讨论了进一步改进的前景。
