CRM1 通过共价键结合和水解莱普霉素 B 抑制核输出。
Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1.
机构信息
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
出版信息
Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1303-8. doi: 10.1073/pnas.1217203110. Epub 2013 Jan 7.
Abstract
The polyketide natural product Leptomycin B inhibits nuclear export mediated by the karyopherin protein chromosomal region maintenance 1 (CRM1). Here, we present 1.8- to 2.0-Å-resolution crystal structures of CRM1 bound to Leptomycin B and related inhibitors Anguinomycin A and Ratjadone A. Structural and complementary chemical analyses reveal an unexpected mechanism of inhibition involving covalent conjugation and CRM1-mediated hydrolysis of the natural products' lactone rings. Furthermore, mutagenesis reveals the mechanism of hydrolysis by CRM1. The nuclear export signal (NES)-binding groove of CRM1 is able to drive a chemical reaction in addition to binding protein cargoes for transport through the nuclear pore complex.
摘要
多酮天然产物 Leptomycin B 通过核输出蛋白核质区保持蛋白 1 (CRM1) 介导的核输出进行抑制。在这里，我们展示了与 Leptomycin B 结合的 CRM1 的 1.8 至 2.0 Å 分辨率晶体结构以及相关抑制剂 Anguinomycin A 和 Ratjadone A。结构和互补化学分析揭示了一种意想不到的抑制机制，涉及共价结合和 CRM1 介导的天然产物内酯环水解。此外，诱变揭示了 CRM1 水解的机制。CRM1 的核输出信号 (NES)-结合槽除了结合运输穿过核孔复合物的蛋白货物外，还能够驱动化学反应。
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