This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

2vag

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Current revision

Crystal structure of di-phosphorylated human CLK1 in complex with a novel substituted indole inhibitor

Structural highlights

2vag is a 1 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 1.8Å
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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

There is a growing recognition of the importance of protein kinases in the control of alternative splicing. To define the underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report the discovery and characterization of the dichloroindolyl enaminonitrile KH-CB19, a potent and highly specific inhibitor of the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4). Cocrystal structures of KH-CB19 with CLK1 and CLK3 revealed a non-ATP mimetic binding mode, conformational changes in helix alphaC and the phosphate binding loop and halogen bonding to the kinase hinge region. KH-CB19 effectively suppressed phosphorylation of SR (serine/arginine) proteins in cells, consistent with its expected mechanism of action. Chemical inhibition of CLK1/CLK4 generated a unique pattern of splicing factor dephosphorylation and had at low nM concentration a profound effect on splicing of the two tissue factor isoforms flTF (full-length TF) and asHTF (alternatively spliced human TF).

Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing.,Fedorov O, Huber K, Eisenreich A, Filippakopoulos P, King O, Bullock AN, Szklarczyk D, Jensen LJ, Fabbro D, Trappe J, Rauch U, Bracher F, Knapp S Chem Biol. 2011 Jan 28;18(1):67-76. PMID:21276940^[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
↑ Fedorov O, Huber K, Eisenreich A, Filippakopoulos P, King O, Bullock AN, Szklarczyk D, Jensen LJ, Fabbro D, Trappe J, Rauch U, Bracher F, Knapp S. Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing. Chem Biol. 2011 Jan 28;18(1):67-76. PMID:21276940 doi:10.1016/j.chembiol.2010.11.009

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2vag"

@@ Line 3: / Line 3: @@
 <StructureSection load='2vag' size='340' side='right'caption='[[2vag]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2vag]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VAG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VAG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2vag]] 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=2VAG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VAG FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=V25:ETHYL+3-[(E)-2-AMINO-1-CYANOETHENYL]-6,7-DICHLORO-1-METHYL-1H-INDOLE-2-CARBOXYLATE'>V25</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]] 1.8&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=V25:ETHYL+3-[(E)-2-AMINO-1-CYANOETHENYL]-6,7-DICHLORO-1-METHYL-1H-INDOLE-2-CARBOXYLATE'>V25</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1z57|1z57]]</div></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=2vag FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vag OCA], [https://pdbe.org/2vag PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vag RCSB], [https://www.ebi.ac.uk/pdbsum/2vag PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vag ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[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>
+[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>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 38: / Line 36: @@
 __TOC__
 </StructureSection>
-[[Category: Dual-specificity kinase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Arrowsmith, C H]]
+[[Category: Arrowsmith CH]]
-[[Category: Bracher, F]]
+[[Category: Bracher F]]
-[[Category: Bullock, A N]]
+[[Category: Bullock AN]]
-[[Category: Delft, F von]]
+[[Category: Edwards A]]
-[[Category: Edwards, A]]
+[[Category: Fedorov O]]
-[[Category: Fedorov, O]]
+[[Category: Huber K]]
-[[Category: Huber, K]]
+[[Category: Knapp S]]
-[[Category: Knapp, S]]
+[[Category: Pike ACW]]
-[[Category: Pike, A C.W]]
+[[Category: Pilka ES]]
-[[Category: Pilka, E S]]
+[[Category: Sundstrom M]]
-[[Category: Sundstrom, M]]
+[[Category: Ugochukwu E]]
-[[Category: Ugochukwu, E]]
+[[Category: Weigelt J]]
-[[Category: Weigelt, J]]
+[[Category: Von Delft F]]
-[[Category: Nucleus]]
-[[Category: Serine/threonine-protein kinase]]
-[[Category: Transferase]]
-[[Category: Tyrosine-protein kinase]]

2vag

From Proteopedia

Current revision

Crystal structure of di-phosphorylated human CLK1 in complex with a novel substituted indole inhibitor

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox