7que: Difference between revisions
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==The STK17A (DRAK1) Kinase Domain Bound to CKJB68== | ==The STK17A (DRAK1) Kinase Domain Bound to CKJB68== | ||
<StructureSection load='7que' size='340' side='right'caption='[[7que]]' scene=''> | <StructureSection load='7que' size='340' side='right'caption='[[7que]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QUE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QUE FirstGlance]. <br> | <table><tr><td colspan='2'>[[7que]] 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=7QUE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QUE FirstGlance]. <br> | ||
</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=7que FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7que OCA], [https://pdbe.org/7que PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7que RCSB], [https://www.ebi.ac.uk/pdbsum/7que PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7que ProSAT]</span></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]] 2.4Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F7I:~{N}-(phenylmethyl)-7,10-dioxa-13,17,18,21-tetrazatetracyclo[12.5.2.1^{2,6}.0^{17,20}]docosa-1(20),2(22),3,5,14(21),15,18-heptaene-5-carboxamide'>F7I</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=7que FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7que OCA], [https://pdbe.org/7que PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7que RCSB], [https://www.ebi.ac.uk/pdbsum/7que PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7que ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/ST17A_HUMAN ST17A_HUMAN] Acts as a positive regulator of apoptosis. Also acts as a regulator of cellular reactive oxygen species.<ref>PMID:21489989</ref> <ref>PMID:9786912</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Serine/threonine kinase 17A (death-associated protein kinase-related apoptosis-inducing protein kinase 1 horizontal line DRAK1) is a part of the death-associated protein kinase (DAPK) family and belongs to the so-called dark kinome. Thus, the current state of knowledge of the cellular function of DRAK1 and its involvement in pathophysiological processes is very limited. Recently, DRAK1 has been implicated in tumorigenesis of glioblastoma multiforme (GBM) and other cancers, but no selective inhibitors of DRAK1 are available yet. To this end, we optimized a pyrazolo[1,5-a]pyrimidine-based macrocyclic scaffold. Structure-guided optimization of this macrocyclic scaffold led to the development of CK156 (34), which displayed high in vitro potency (KD = 21 nM) and selectivity in kinomewide screens. Crystal structures demonstrated that CK156 (34) acts as a type I inhibitor. However, contrary to studies using genetic knockdown of DRAK1, we have seen the inhibition of cell growth of glioma cells in 2D and 3D culture only at low micromolar concentrations. | |||
Illuminating the Dark: Highly Selective Inhibition of Serine/Threonine Kinase 17A with Pyrazolo[1,5-a]pyrimidine-Based Macrocycles.,Kurz CG, Preuss F, Tjaden A, Cusack M, Amrhein JA, Chatterjee D, Mathea S, Berger LM, Berger BT, Kramer A, Weller M, Weiss T, Muller S, Knapp S, Hanke T J Med Chem. 2022 Jun 9;65(11):7799-7817. doi: 10.1021/acs.jmedchem.2c00173. Epub , 2022 May 24. PMID:35608370<ref>PMID:35608370</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7que" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Amrhein JA]] | [[Category: Amrhein JA]] | ||
Latest revision as of 16:23, 1 February 2024
The STK17A (DRAK1) Kinase Domain Bound to CKJB68The STK17A (DRAK1) Kinase Domain Bound to CKJB68
Structural highlights
FunctionST17A_HUMAN Acts as a positive regulator of apoptosis. Also acts as a regulator of cellular reactive oxygen species.[1] [2] Publication Abstract from PubMedSerine/threonine kinase 17A (death-associated protein kinase-related apoptosis-inducing protein kinase 1 horizontal line DRAK1) is a part of the death-associated protein kinase (DAPK) family and belongs to the so-called dark kinome. Thus, the current state of knowledge of the cellular function of DRAK1 and its involvement in pathophysiological processes is very limited. Recently, DRAK1 has been implicated in tumorigenesis of glioblastoma multiforme (GBM) and other cancers, but no selective inhibitors of DRAK1 are available yet. To this end, we optimized a pyrazolo[1,5-a]pyrimidine-based macrocyclic scaffold. Structure-guided optimization of this macrocyclic scaffold led to the development of CK156 (34), which displayed high in vitro potency (KD = 21 nM) and selectivity in kinomewide screens. Crystal structures demonstrated that CK156 (34) acts as a type I inhibitor. However, contrary to studies using genetic knockdown of DRAK1, we have seen the inhibition of cell growth of glioma cells in 2D and 3D culture only at low micromolar concentrations. Illuminating the Dark: Highly Selective Inhibition of Serine/Threonine Kinase 17A with Pyrazolo[1,5-a]pyrimidine-Based Macrocycles.,Kurz CG, Preuss F, Tjaden A, Cusack M, Amrhein JA, Chatterjee D, Mathea S, Berger LM, Berger BT, Kramer A, Weller M, Weiss T, Muller S, Knapp S, Hanke T J Med Chem. 2022 Jun 9;65(11):7799-7817. doi: 10.1021/acs.jmedchem.2c00173. Epub , 2022 May 24. PMID:35608370[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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