6m6x

Oridonin in complex with CRM1#-Ran-RanBP1

spinqualitylabelsall models 6m6x, resolution 2.88Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6m6x is a 3 chain structure with sequence from Homo sapiens and Saccharomyces cerevisiae S288C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.88Å Ligands: CL, EDO, GTP, MG, ODN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function RAN_HUMAN GTP-binding protein involved in nucleocytoplasmic transport. Required for the import of protein into the nucleus and also for RNA export. Involved in chromatin condensation and control of cell cycle (By similarity). The complex with BIRC5/ survivin plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules. Acts as a negative regulator of the kinase activity of VRK1 and VRK2. Enhances AR-mediated transactivation. Transactivation decreases as the poly-Gln length within AR increases. Publication Abstract from PubMed 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. Novel Mechanistic Observations and NES-Binding Groove Features Revealed by the CRM1 Inhibitors Plumbagin and Oridonin.,Lei Y, Li Y, Tan Y, Qian Z, Zhou Q, Jia D, Sun Q J Nat Prod. 2021 May 28;84(5):1478-1488. doi: 10.1021/acs.jnatprod.0c01231. Epub , 2021 Apr 23. PMID:33890470 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Exportin 3D structures

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