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5x8i

From Proteopedia

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Current revision

Crystal structure of human CLK1 in complex with compound 25

Structural highlights

5x8i is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.902Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CLK1_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, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA.^[1] ^[2]

Publication Abstract from PubMed

Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compound 25 was solved, and the potency and kinase selectivity of compound 25 were interpreted. Compound 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compound 25 could be used as a chemical probe or agent in future mechanism-of-action or autophagy-related disease therapy studies.

Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers.,Sun QZ, Lin GF, Li LL, Jin XT, Huang LY, Zhang G, Yang W, Chen K, Xiang R, Chen C, Wei YQ, Lu GW, Yang SY J Med Chem. 2017 Jul 27;60(14):6337-6352. doi: 10.1021/acs.jmedchem.7b00665. Epub, 2017 Jul 17. PMID:28692292^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Moeslein FM, Myers MP, Landreth GE. The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. J Biol Chem. 1999 Sep 17;274(38):26697-704. PMID:10480872
↑ 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
↑ Sun QZ, Lin GF, Li LL, Jin XT, Huang LY, Zhang G, Yang W, Chen K, Xiang R, Chen C, Wei YQ, Lu GW, Yang SY. Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers. J Med Chem. 2017 Jul 27;60(14):6337-6352. doi: 10.1021/acs.jmedchem.7b00665. Epub, 2017 Jul 17. PMID:28692292 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00665

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5x8i"

@@ Line 3: / Line 3: @@
 <StructureSection load='5x8i' size='340' side='right'caption='[[5x8i]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5x8i]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5X8I OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5X8I FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5x8i]] is a 2 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=5X8I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5X8I FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SQZ:5-[1-[(1S)-1-(4-fluorophenyl)ethyl]-[1,2,3]triazolo[4,5-c]quinolin-8-yl]-1,3-benzoxazole'>SQZ</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]] 1.902&#8491;</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=SQZ:5-[1-[(1S)-1-(4-fluorophenyl)ethyl]-[1,2,3]triazolo[4,5-c]quinolin-8-yl]-1,3-benzoxazole'>SQZ</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5x8i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x8i OCA], [http://pdbe.org/5x8i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5x8i RCSB], [http://www.ebi.ac.uk/pdbsum/5x8i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5x8i 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=5x8i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x8i OCA], [https://pdbe.org/5x8i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5x8i RCSB], [https://www.ebi.ac.uk/pdbsum/5x8i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5x8i ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/CLK1_HUMAN CLK1_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, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA.<ref>PMID:10480872</ref> <ref>PMID:19168442</ref>
+[https://www.uniprot.org/uniprot/CLK1_HUMAN CLK1_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, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA.<ref>PMID:10480872</ref> <ref>PMID:19168442</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Dual-specificity kinase]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Huang, L Y]]
+[[Category: Huang LY]]
-[[Category: Jin, X T]]
+[[Category: Jin XT]]
-[[Category: Li, L L]]
+[[Category: Li LL]]
-[[Category: Lin, G F]]
+[[Category: Lin GF]]
-[[Category: Lu, G W]]
+[[Category: Lu GW]]
-[[Category: Sun, Q Z]]
+[[Category: Sun QZ]]
-[[Category: Wei, Y Q]]
+[[Category: Wei YQ]]
-[[Category: Yang, S Y]]
+[[Category: Yang SY]]
-[[Category: Zhang, G]]
+[[Category: Zhang G]]
-[[Category: Clk1]]
-[[Category: Complex]]
-[[Category: Inhibitor]]
-[[Category: Kinase]]
-[[Category: Transferase-transferase inhibitor complex]]

5x8i

From Proteopedia

Current revision

Crystal structure of human CLK1 in complex with compound 25

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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