8hq6

KL2 in complex with CRM1-Ran-RanBP1

spinqualitylabelsall models 8hq6, resolution 2.03Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8hq6 is a 3 chain structure with sequence from Homo sapiens and Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.03Å Ligands: CL, DMS, GLU, GOL, GTP, MFF, MG, NO3 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 Cancer cells frequently utilize elevated nuclear export to escape tumor suppression and gain proliferative advantage. Chromosome Region Maintenance 1 (CRM1/XPO1) mediates macromolecule nuclear export and plays an important role in tumorigenesis and progression. The clinical approval of its covalent inhibitor KPT-330 (Selinexor) validates the feasibility of targeting CRM1 to treat cancers. Here, we synthesized four aminoratjadone derivatives and found that two of them, KL1 and KL2, are noncovalent CRM1 inhibitors. The two compounds underwent spontaneous hydrolysis in aqueous buffers, and the resulting products were more active against CRM1. High-resolution crystal structures revealed the CRM1-binding mode of these compounds and explained the observed structure-activity relationships. In cells, KL1 and KL2 localized CRM1 in the nuclear periphery and led to depletion of nuclear CRM1, thereby inhibiting the nuclear export and growth of colorectal cancer cells at submicromolar concentrations. This work lays the foundation for further development of aminoratjadone-based noncovalent CRM1 inhibitors. Discovery of Aminoratjadone Derivatives as Potent Noncovalent CRM1 Inhibitors.,Jian L, Zscherp R, Beutling U, Shen X, Xu S, Zhang X, Bronstrup M, Klahn P, Sun Q J Med Chem. 2023 Sep 14;66(17):11940-11950. doi: 10.1021/acs.jmedchem.3c00549. , Epub 2023 Aug 18. PMID:37595020 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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