6fyv
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==X-RAY STRUCTURE OF CLK4-KD(146-480)/CX-4945 AT 2.46A== | |
| + | <StructureSection load='6fyv' size='340' side='right' caption='[[6fyv]], [[Resolution|resolution]] 2.46Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6fyv]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FYV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FYV FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3NG:5-[(3-CHLOROPHENYL)AMINO]BENZO[C][2,6]NAPHTHYRIDINE-8-CARBOXYLIC+ACID'>3NG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6fyi|6fyi]], [[6fyk|6fyk]], [[6fyl|6fyl]], [[6fyo|6fyo]], [[6fyp|6fyp]], [[6fyr|6fyr]]</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </span></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=6fyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fyv OCA], [http://pdbe.org/6fyv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fyv RCSB], [http://www.ebi.ac.uk/pdbsum/6fyv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fyv ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/CLK4_HUMAN CLK4_HUMAN]] Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates SRSF1 and SRSF3. Required for the regulation of alternative splicing of MAPT/TAU. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.<ref>PMID:11170754</ref> <ref>PMID:19168442</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan-McDermid syndrome (PMDS). Herein, we report the discovery of a very potent indazole CLK inhibitor series, and the CLK2 X-ray structure of its most potent analog. This new indazole series was identified via a biochemical CLK2 Caliper assay screen with 30k compounds that were selected by an in silico approach. Novel high resolution X-ray structures of all CLKs, including the first CLK4 X-ray structure, bound to known CLK2 inhibitor tool compounds (e.g. TG003, CX-4945), are also shown and yield insights into inhibitor selectivity in the CLK family. Efficacy of our new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. We show genotoxicity findings in the human lymphocyte MNT assay using two structurally different CLK inhibitors, which reveals a major concern for pan-CLK inhibition in PMDS. | ||
| - | + | X-ray structures and feasibility assessment of CLK2 inhibitors for Phelan McDermid syndrome.,Lerchner AM, Kallen J, Bergsdorf C, Arnaud B, Bernhard M, Brichet M, Cobos-Correa A, Elhajouji A, Freuler F, Galimberti I, Guibourdenche C, Haenni S, Holzinger S, Hunziker J, Izaac A, Kaufmann M, Leder L, Martus HJ, von Matt P, Polyakov V, Roethlisberger P, Roma G, Stiefl N, Uteng M ChemMedChem. 2018 Jul 9. doi: 10.1002/cmdc.201800344. PMID:29985556<ref>PMID:29985556</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6fyv" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Dual-specificity kinase]] | ||
[[Category: Kallen, J]] | [[Category: Kallen, J]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Phosphotransferase]] | ||
| + | [[Category: Splicing]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 07:42, 18 July 2018
X-RAY STRUCTURE OF CLK4-KD(146-480)/CX-4945 AT 2.46A
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