5jlj
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal Structure of KPT8602 in complex with CRM1-Ran-RanBP1== | |
| + | <StructureSection load='5jlj' size='340' side='right' caption='[[5jlj]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5jlj]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JLJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JLJ FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6L8:(2R)-3-{3-[3,5-BIS(TRIFLUOROMETHYL)PHENYL]-1H-1,2,4-TRIAZOL-1-YL}-2-(PYRIMIDIN-5-YL)PROPANAMIDE'>6L8</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5jlj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jlj OCA], [http://pdbe.org/5jlj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jlj RCSB], [http://www.ebi.ac.uk/pdbsum/5jlj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jlj ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/RAN_HUMAN 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.<ref>PMID:10400640</ref> <ref>PMID:8692944</ref> <ref>PMID:18591255</ref> <ref>PMID:18617507</ref> Enhances AR-mediated transactivation. Transactivation decreases as the poly-Gln length within AR increases.<ref>PMID:10400640</ref> <ref>PMID:8692944</ref> <ref>PMID:18591255</ref> <ref>PMID:18617507</ref> [[http://www.uniprot.org/uniprot/XPO1_YEAST XPO1_YEAST]] Receptor for the leucine-rich nuclear export signal (NES). [[http://www.uniprot.org/uniprot/YRB1_YEAST YRB1_YEAST]] Important for the export of protein containing nuclear export signal (NES) out of the nucleus. Stimulates the GTPase activity of GSP1 and GSP2. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.Leukemia advance online publication, 21 June 2016; doi:10.1038/leu.2016.136. | ||
| - | + | Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies.,Hing ZA, Fung HY, Ranganathan P, Mitchell S, El-Gamal D, Woyach JA, Williams K, Goettl VM, Smith J, Yu X, Meng X, Sun Q, Cagatay T, Lehman AM, Lucas DM, Baloglu E, Shacham S, Kauffman MG, Byrd JC, Chook YM, Garzon R, Lapalombella R Leukemia. 2016 Jun 21. doi: 10.1038/leu.2016.136. PMID:27323910<ref>PMID:27323910</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | [[Category: Chook, Y | + | <div class="pdbe-citations 5jlj" style="background-color:#fffaf0;"></div> |
| - | [[Category: Fung, H | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Chook, Y M]] | ||
| + | [[Category: Fung, H Y]] | ||
| + | [[Category: Exportin-1]] | ||
| + | [[Category: Heat repeat]] | ||
| + | [[Category: Nuclear transport]] | ||
| + | [[Category: Protein transport]] | ||
| + | [[Category: Transport receptor-inhibitor complex]] | ||
Revision as of 10:27, 13 July 2016
Crystal Structure of KPT8602 in complex with CRM1-Ran-RanBP1
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