Fung Ho Yee Joyce, Chook Yuh Min
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park, Dallas, TX 75390-9041, USA.
Semin Cancer Biol. 2014 Aug;27:52-61. doi: 10.1016/j.semcancer.2014.03.002. Epub 2014 Mar 12.
CRM1 or XPO1 is the major nuclear export receptor in the cell, which controls the nuclear-cytoplasmic localization of many proteins and RNAs. CRM1 is also a promising cancer drug target as the transport receptor is overexpressed in many cancers where some of its cargos are misregulated and mislocalized to the cytoplasm. Atomic level understanding of CRM1 function has greatly facilitated recent drug discovery and development of CRM1 inhibitors to target a variety of malignancies. Numerous atomic resolution CRM1 structures are now available, explaining how the exporter recognizes nuclear export signals in its cargos, how RanGTP and cargo bind with positive cooperativity, how RanBP1 causes release of export cargos in the cytoplasm and how diverse inhibitors such as Leptomycin B and the new KPT-SINE compounds block nuclear export. This review summarizes structure-function studies that explain CRM1-cargo recognition, release and inhibition.
CRM1（也称为XPO1）是细胞中的主要核输出受体，它控制着许多蛋白质和RNA的核质定位。CRM1也是一个很有前景的癌症药物靶点，因为这种转运受体在许多癌症中过度表达，其一些货物被错误调节并错误定位于细胞质中。对CRM1功能的原子水平理解极大地促进了最近针对各种恶性肿瘤的CRM1抑制剂的药物发现和开发。现在有许多原子分辨率的CRM1结构，解释了输出蛋白如何识别其货物中的核输出信号、RanGTP和货物如何以正协同作用结合、RanBP1如何导致输出货物在细胞质中释放，以及诸如雷帕霉素B和新型KPT-SINE化合物等多种抑制剂如何阻断核输出。本综述总结了解释CRM1-货物识别、释放和抑制的结构-功能研究。
