4gpt
From Proteopedia
Crystal structure of KPT251 in complex with CRM1-Ran-RanBP1
Structural highlights
FunctionRAN_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.[1] [2] [3] [4] Enhances AR-mediated transactivation. Transactivation decreases as the poly-Gln length within AR increases.[5] [6] [7] [8] Publication Abstract from PubMedDrugs that target the chief mediator of nuclear export, chromosome region maintenance 1 protein (CRM1) have potential as therapeutics for leukemia, but existing CRM1 inhibitors show variable potencies and a broad range of cytotoxic effects. Here we report the structural analysis and antileukemic activity of a new generation of small-molecule inhibitors of CRM1. Designated SINE, these compounds were developed using molecular modeling to screen a small virtual library of compounds against the NES groove of CRM1. The 2.2 A crystal structure of the CRM1-Ran-RanBP1 complex bound to KPT-251, a representative molecule of this class of inhibitors, shows that the drug occupies part of the groove in CRM1 that is usually occupied by the nuclear export signal (NES), but penetrates much deeper into the groove and blocks CRM1-directed protein export. SINE inhibitors exhibit potent anti-leukemic activity, inducing apoptosis at nanomolar concentrations in a panel of 14 human acute myeloid leukemia (AML) cell lines representing different molecular subtypes of the disease. When administered orally to immunodeficient mice engrafted with human AML cells, KPT-251 had potent antileukemic activity with negligible toxicity to normal hematopoietic cells. Thus, KPT-SINE CRM1 antagonists represent a novel class of drugs that warrant further testing in AML patients.Leukemia accepted article preview online, 31 July 2012; doi:10.1038/leu.2012.219. Anti-leukemic activity of nuclear export inhibitors that spare normal hematopoietic cells.,Etchin J, Sun Q, Kentsis A, Farmer A, Zhang ZC, Sanda T, Mansour MR, Barcelo C, McCauley D, Kauffman M, Shacham S, Christie AL, Kung AL, Rodig SJ, Chook YM, Look AT Leukemia. 2012 Jul 31. doi: 10.1038/leu.2012.219. PMID:22847027[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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