4gpt

Crystal structure of KPT251 in complex with CRM1-Ran-RanBP1Crystal structure of KPT251 in complex with CRM1-Ran-RanBP1

Structural highlights 4gpt 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 2.22Å Ligands: , , , , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Drugs 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Exportin 3D structures GTP-binding protein 3D structures

spinqualitylabelsall models 4gpt, resolution 2.22Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image