Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, United States.
Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, United States.
Curr Opin Chem Biol. 2019 Jun;50:45-54. doi: 10.1016/j.cbpa.2019.02.019. Epub 2019 Mar 23.
The AAA proteins are a family of enzymes that play key roles in diverse dynamic cellular processes, ranging from proteostasis to directional intracellular transport. Dysregulation of AAA proteins has been linked to several diseases, including cancer, suggesting a possible therapeutic role for inhibitors of these enzymes. In the past decade, new chemical probes have been developed for AAA proteins including p97, dynein, midasin, and ClpC1. In this review, we discuss how these compounds have been used to study the cellular functions and conformational dynamics of AAA proteins. We discuss future directions for inhibitor development and early efforts to utilize AAA protein inhibitors in the clinical setting.
AAA 蛋白是一类在多种动态细胞过程中发挥关键作用的酶，范围从蛋白质稳态到定向的细胞内运输。AAA 蛋白的失调与包括癌症在内的几种疾病有关，这表明这些酶的抑制剂可能具有治疗作用。在过去的十年中，已经开发出了针对 p97、动力蛋白、中间丝和 ClpC1 等 AAA 蛋白的新型化学探针。在这篇综述中，我们讨论了这些化合物如何被用于研究 AAA 蛋白的细胞功能和构象动力学。我们讨论了抑制剂开发的未来方向以及在临床环境中利用 AAA 蛋白抑制剂的早期努力。
