6yty: Difference between revisions
New page: '''Unreleased structure''' The entry 6yty is ON HOLD Authors: Schroeder, M., Chaikuad, A., Knapp, S., Structural Genomics Consortium (SGC) Description: CLK3 A319V mutant bound with ben... |
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==CLK3 A319V mutant bound with benzothiazole Tg003 (Cpd 2)== | |||
<StructureSection load='6yty' size='340' side='right'caption='[[6yty]], [[Resolution|resolution]] 1.76Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6yty]] 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=6YTY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YTY FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.76Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EAE:(1~{Z})-1-(3-ethyl-5-methoxy-1,3-benzothiazol-2-ylidene)propan-2-one'>EAE</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></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=6yty FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yty OCA], [https://pdbe.org/6yty PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yty RCSB], [https://www.ebi.ac.uk/pdbsum/6yty PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yty ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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;"> | |||
== Publication Abstract from PubMed == | |||
Selectivity remains a challenge for ATP-mimetic kinase inhibitors, an issue that may be overcome by targeting unique residues or binding pockets. However, to date only few strategies have been developed. Here we identify that bulky residues located N-terminal to the DFG motif (DFG-1) represent an opportunity for designing highly selective inhibitors with unexpected binding modes. We demonstrate that several diverse inhibitors exerted selective, noncanonical binding modes that exclusively target large hydrophobic DFG-1 residues present in many kinases including PIM, CK1, DAPK, and CLK. By use of the CLK family as a model, structural and biochemical data revealed that the DFG-1 valine controlled a noncanonical binding mode in CLK1, providing a rationale for selectivity over the closely related CLK3 which harbors a smaller DFG-1 alanine. Our data suggest that targeting the restricted back pocket in the small fraction of kinases that harbor bulky DFG-1 residues offers a versatile selectivity filter for inhibitor design. | |||
DFG-1 Residue Controls Inhibitor Binding Mode and Affinity, Providing a Basis for Rational Design of Kinase Inhibitor Selectivity.,Schroder M, Bullock AN, Fedorov O, Bracher F, Chaikuad A, Knapp S J Med Chem. 2020 Sep 24;63(18):10224-10234. doi: 10.1021/acs.jmedchem.0c00898., Epub 2020 Aug 27. PMID:32787076<ref>PMID:32787076</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6yty" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: Schroeder | *[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Chaikuad A]] | |||
[[Category: Knapp S]] | |||
[[Category: Schroeder M]] | |||
Latest revision as of 16:35, 24 January 2024
CLK3 A319V mutant bound with benzothiazole Tg003 (Cpd 2)CLK3 A319V mutant bound with benzothiazole Tg003 (Cpd 2)
Structural highlights
FunctionCLK3_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 PubMedSelectivity remains a challenge for ATP-mimetic kinase inhibitors, an issue that may be overcome by targeting unique residues or binding pockets. However, to date only few strategies have been developed. Here we identify that bulky residues located N-terminal to the DFG motif (DFG-1) represent an opportunity for designing highly selective inhibitors with unexpected binding modes. We demonstrate that several diverse inhibitors exerted selective, noncanonical binding modes that exclusively target large hydrophobic DFG-1 residues present in many kinases including PIM, CK1, DAPK, and CLK. By use of the CLK family as a model, structural and biochemical data revealed that the DFG-1 valine controlled a noncanonical binding mode in CLK1, providing a rationale for selectivity over the closely related CLK3 which harbors a smaller DFG-1 alanine. Our data suggest that targeting the restricted back pocket in the small fraction of kinases that harbor bulky DFG-1 residues offers a versatile selectivity filter for inhibitor design. DFG-1 Residue Controls Inhibitor Binding Mode and Affinity, Providing a Basis for Rational Design of Kinase Inhibitor Selectivity.,Schroder M, Bullock AN, Fedorov O, Bracher F, Chaikuad A, Knapp S J Med Chem. 2020 Sep 24;63(18):10224-10234. doi: 10.1021/acs.jmedchem.0c00898., Epub 2020 Aug 27. PMID:32787076[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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