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6q8p

From Proteopedia

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Current revision

Structure of CLK1 with bound N-methyl-10-nitropyrido[3,4-g]quinazolin-2-amine

Structural highlights

6q8p is a 3 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 3Å
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

Cdc2-like kinase 1 (CLK1) and dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) are involved in the regulation of alternative pre-mRNA splicing. Dysregulation of this process has been linked to cancer progression and neurodegenerative diseases, making CLK1 and DYRK1A important therapeutic targets. Here we describe the synthesis of new pyrido[3,4-g]quinazoline derivatives and the evaluation of the inhibitory potencies of these compounds toward CDK5, CK1, GSK3, CLK1 and DYRK1A. Introduction of aminoalkylamino groups at the 2-position resulted in several compounds with low nanomolar affinity and selective inhibition of CLK1 and/or DYRK1A. Their evaluation on several immortalized or cancerous cell lines showed varying degree of cell viability reduction. Co-crystal structures of CLK1 with two of the most potent compounds revealed two alternative binding modes of the pyrido[3,4-g]quinazoline scaffold that can be exploited for future inhibitor design.

New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis.,Tazarki H, Zeinyeh W, Esvan YJ, Knapp S, Chatterjee D, Schroder M, Joerger AC, Khiari J, Josselin B, Baratte B, Bach S, Ruchaud S, Anizon F, Giraud F, Moreau P Eur J Med Chem. 2019 Jan 26;166:304-317. doi: 10.1016/j.ejmech.2019.01.052. PMID:30731399^[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
↑ Tazarki H, Zeinyeh W, Esvan YJ, Knapp S, Chatterjee D, Schroder M, Joerger AC, Khiari J, Josselin B, Baratte B, Bach S, Ruchaud S, Anizon F, Giraud F, Moreau P. New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis. Eur J Med Chem. 2019 Jan 26;166:304-317. doi: 10.1016/j.ejmech.2019.01.052. PMID:30731399 doi:http://dx.doi.org/10.1016/j.ejmech.2019.01.052

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/6q8p"

@@ Line 1: / Line 1: @@
 ==Structure of CLK1 with bound N-methyl-10-nitropyrido[3,4-g]quinazolin-2-amine==
-<StructureSection load='6q8p' size='340' side='right' caption='[[6q8p]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
+<StructureSection load='6q8p' size='340' side='right'caption='[[6q8p]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6q8p]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q8P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6Q8P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6q8p]] is a 3 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=6Q8P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Q8P FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HQB:~{N}-methyl-10-nitro-pyrido[3,4-g]quinazolin-2-amine'>HQB</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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]] 3&#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=HQB:~{N}-methyl-10-nitro-pyrido[3,4-g]quinazolin-2-amine'>HQB</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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=6q8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q8p OCA], [http://pdbe.org/6q8p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q8p RCSB], [http://www.ebi.ac.uk/pdbsum/6q8p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q8p 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=6q8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q8p OCA], [https://pdbe.org/6q8p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6q8p RCSB], [https://www.ebi.ac.uk/pdbsum/6q8p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6q8p 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 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 6q8p" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Dual-specificity kinase]]
+[[Category: Homo sapiens]]
-[[Category: Anizon, F]]
+[[Category: Large Structures]]
-[[Category: Bach, S]]
+[[Category: Anizon F]]
-[[Category: Baratte, B]]
+[[Category: Bach S]]
-[[Category: Chatterjee, D]]
+[[Category: Baratte B]]
-[[Category: Esvan, Y J]]
+[[Category: Chatterjee D]]
-[[Category: Giraud, F]]
+[[Category: Esvan YJ]]
-[[Category: Joerger, A C]]
+[[Category: Giraud F]]
-[[Category: Josselin, B]]
+[[Category: Joerger AC]]
-[[Category: Khiari, J]]
+[[Category: Josselin B]]
-[[Category: Knapp, S]]
+[[Category: Khiari J]]
-[[Category: Moreau, P]]
+[[Category: Knapp S]]
-[[Category: Ruchaud, S]]
+[[Category: Moreau P]]
-[[Category: Structural genomic]]
+[[Category: Ruchaud S]]
-[[Category: Schroeder, M]]
+[[Category: Schroeder M]]
-[[Category: Tazarki, H]]
+[[Category: Tazarki H]]
-[[Category: Zeinyeh, W]]
+[[Category: Zeinyeh W]]
-[[Category: Inhibitor]]
-[[Category: Nucleus]]
-[[Category: Serine/threonine-protein kinase]]
-[[Category: Sgc]]
-[[Category: Transferase]]
-[[Category: Tyrosine-protein kinase]]

6q8p

From Proteopedia

Current revision

Structure of CLK1 with bound N-methyl-10-nitropyrido[3,4-g]quinazolin-2-amine

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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