Lei Yuqin, Li Yuling, Tan Yuping, Qian Zhiyong, Zhou Qiao, Jia Da, Sun Qingxiang
Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre of Biotherapy, Chengdu 610041, People's Republic of China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatrics, Division of Neurology, West China Second University Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
J Nat Prod. 2021 May 28;84(5):1478-1488. doi: 10.1021/acs.jnatprod.0c01231. Epub 2021 Apr 23.
The protein chromosome region maintenance 1 (CRM1) is an important nuclear export factor and drug target in diseases such as cancer and viral infections. Several plant-derived CRM1 inhibitors including plumbagin and oridonin possess potent antitumor activities. However, their modes of CRM1 inhibition remain unclear. Here, a multimutant CRM1 was engineered to enable crystallization of these two small molecules in its NES groove. Plumbagin and oridonin share the same three conjugation sites in CRM1. In solution, these two inhibitors targeted more CRM1 sites and inhibited its activity through promoting its aggregation, in addition to directly targeting the NES groove. While the plumbagin-bound NES groove resembles the NES-bound groove state, the oridonin complex reveals for the first time a more open NES groove. The observed greater NES groove dynamics may improve cargo loading through a "capture-and-tighten" mechanism. This work thus provides new insights on the mechanism of CRM1 inhibition by two natural products and a structural basis for further development of these or other CRM1 inhibitors.
蛋白质染色体区域维持蛋白1（CRM1）是一种重要的核输出因子，也是癌症和病毒感染等疾病中的药物靶点。包括白花丹素和冬凌草甲素在内的几种植物来源的CRM1抑制剂具有强大的抗肿瘤活性。然而，它们抑制CRM1的模式仍不清楚。在此，构建了一种多突变CRM1，以使这两种小分子在其核输出信号（NES）凹槽中结晶。白花丹素和冬凌草甲素在CRM1中具有相同的三个结合位点。在溶液中，这两种抑制剂除了直接靶向NES凹槽外，还靶向更多的CRM1位点，并通过促进其聚集来抑制其活性。虽然白花丹素结合的NES凹槽类似于NES结合的凹槽状态，但冬凌草甲素复合物首次揭示了一个更开放的NES凹槽。观察到的更大的NES凹槽动态性可能通过“捕获并收紧”机制改善货物装载。因此，这项工作为两种天然产物抑制CRM1的机制提供了新的见解，并为进一步开发这些或其他CRM1抑制剂提供了结构基础。
