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| | <StructureSection load='6khf' size='340' side='right'caption='[[6khf]], [[Resolution|resolution]] 2.60Å' scene=''> | | <StructureSection load='6khf' size='340' side='right'caption='[[6khf]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6khf]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KHF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KHF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6khf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KHF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KHF 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></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.598Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3NG:5-[(3-CHLOROPHENYL)AMINO]BENZO[C][2,6]NAPHTHYRIDINE-8-CARBOXYLIC+ACID'>3NG</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=6khf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6khf OCA], [http://pdbe.org/6khf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6khf RCSB], [http://www.ebi.ac.uk/pdbsum/6khf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6khf ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6khf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6khf OCA], [https://pdbe.org/6khf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6khf RCSB], [https://www.ebi.ac.uk/pdbsum/6khf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6khf ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CLK3_HUMAN CLK3_HUMAN]] Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Phosphorylates SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.<ref>PMID:9637771</ref> <ref>PMID:19168442</ref> | + | [https://www.uniprot.org/uniprot/CLK3_HUMAN CLK3_HUMAN] Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Phosphorylates SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.<ref>PMID:9637771</ref> <ref>PMID:19168442</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6khf" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6khf" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dual-specificity kinase]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Chang, J H]] | + | [[Category: Chang JH]] |
| - | [[Category: Jin, H]] | + | [[Category: Jin H]] |
| - | [[Category: Lee, J Y]] | + | [[Category: Lee JY]] |
| - | [[Category: Yun, J S]] | + | [[Category: Yun JS]] |
| - | [[Category: Alternative splicing]]
| + | |
| - | [[Category: Casein kinase]]
| + | |
| - | [[Category: Cdc2-like kinase]]
| + | |
| - | [[Category: Cx-4945]]
| + | |
| - | [[Category: Splicing]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
CLK3_HUMAN Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Phosphorylates SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.[1] [2]
Publication Abstract from PubMed
Cdc2-like kinases (CLKs) play a crucial role in the alternative splicing of eukaryotic pre-mRNAs through the phosphorylation of serine/arginine-rich proteins (SR proteins). Dysregulation of this processes is linked with various diseases including cancers, neurodegenerative diseases, and many genetic diseases. Thus, CLKs have been regarded to have a potential as a therapeutic target and significant efforts have been exerted to discover an effective inhibitor. In particular, the small molecule CX-4945, originally identified as an inhibitor of casein kinase 2 (CK2), was further revealed to have a strong CLK-inhibitory activity. Four isoforms of CLKs (CLK1, CLK2, CLK3, and CLK4) can be inhibited by CX-4945, with the highest inhibitory effect on CLK2. This study aimed to elucidate the structural basis of the selective inhibitory effect of CX-4945 on different isoforms of CLKs. We determined the crystal structures of CLK1, CLK2, and CLK3 in complex with CX-4945 at resolutions of 2.4 A, 2.8 A, and 2.6 A, respectively. Comparative analysis revealed that CX-4945 was bound in the same active site pocket of the CLKs with similar interacting networks. Intriguingly, the active sites of CLK/CX-4945 complex structures had different sizes and electrostatic surface charge distributions. The active site of CLK1 was somewhat narrow and contained a negatively charged patch. CLK3 had a protruded Lys248 residue in the entrance of the active site pocket. In addition, Ala319, equivalent to Val324 (CLK1) and Val326 (CLK2), contributed to the weak hydrophobic interactions with the benzonaphthyridine ring of CX-4945. In contrast, the charge distribution pattern of CLK2 was the weakest, favoring its interactions with benzonaphthyridine ring. Thus, the relatively strong binding affinities of CX-4945 with CLK2 are consistent with its strong inhibitory effect defined in the previous study. These results may provide insights into structure-based drug discovery processes.
Structural Basis for the Selective Inhibition of Cdc2-Like Kinases by CX-4945.,Lee JY, Yun JS, Kim WK, Chun HS, Jin H, Cho S, Chang JH Biomed Res Int. 2019 Aug 18;2019:6125068. doi: 10.1155/2019/6125068. eCollection , 2019. PMID:31531359[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Duncan PI, Stojdl DF, Marius RM, Scheit KH, Bell JC. The Clk2 and Clk3 dual-specificity protein kinases regulate the intranuclear distribution of SR proteins and influence pre-mRNA splicing. Exp Cell Res. 1998 Jun 15;241(2):300-8. PMID:9637771 doi:http://dx.doi.org/S0014-4827(98)94083-6
- ↑ Eisenreich A, Bogdanov VY, Zakrzewicz A, Pries A, Antoniak S, Poller W, Schultheiss HP, Rauch U. Cdc2-like kinases and DNA topoisomerase I regulate alternative splicing of tissue factor in human endothelial cells. Circ Res. 2009 Mar 13;104(5):589-99. doi: 10.1161/CIRCRESAHA.108.183905. Epub, 2009 Jan 22. PMID:19168442 doi:10.1161/CIRCRESAHA.108.183905
- ↑ Lee JY, Yun JS, Kim WK, Chun HS, Jin H, Cho S, Chang JH. Structural Basis for the Selective Inhibition of Cdc2-Like Kinases by CX-4945. Biomed Res Int. 2019 Aug 18;2019:6125068. doi: 10.1155/2019/6125068. eCollection , 2019. PMID:31531359 doi:http://dx.doi.org/10.1155/2019/6125068
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