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==Crystal Structure of human Serine/Threonine Kinase 17B (STK17B) in complex with Quercetin== | ==Crystal Structure of human Serine/Threonine Kinase 17B (STK17B) in complex with Quercetin== | ||
<StructureSection load='3lm5' size='340' side='right' caption='[[3lm5]], [[Resolution|resolution]] 2.29Å' scene=''> | <StructureSection load='3lm5' size='340' side='right'caption='[[3lm5]], [[Resolution|resolution]] 2.29Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3lm5]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3lm5]] 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=3LM5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3LM5 FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.29Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QUE:3,5,7,3,4-PENTAHYDROXYFLAVONE'>QUE</scene></td></tr> | |||
<tr id=' | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3lm5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lm5 OCA], [https://pdbe.org/3lm5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3lm5 RCSB], [https://www.ebi.ac.uk/pdbsum/3lm5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3lm5 ProSAT]</span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/ST17B_HUMAN ST17B_HUMAN] Phosphorylates myosin light chains (By similarity). Acts as a positive regulator of apoptosis.<ref>PMID:9786912</ref> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
Check<jmol> | Check<jmol> | ||
<jmolCheckbox> | <jmolCheckbox> | ||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/lm/3lm5_consurf.spt"</scriptWhenChecked> | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/lm/3lm5_consurf.spt"</scriptWhenChecked> | ||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </jmolCheckbox> | ||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/ | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3lm5 ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
STK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied "dark" kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1. | |||
A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation.,Picado A, Chaikuad A, Wells CI, Shrestha S, Zuercher WJ, Pickett JE, Kwarcinski FE, Sinha P, de Silva CS, Zutshi R, Liu S, Kannan N, Knapp S, Drewry DH, Willson TM J Med Chem. 2020 Dec 10;63(23):14626-14646. doi: 10.1021/acs.jmedchem.0c01174., Epub 2020 Nov 20. PMID:33215924<ref>PMID:33215924</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3lm5" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Serine/threonine protein kinase|Serine/threonine protein kinase]] | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 29: | Line 37: | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Arrowsmith | [[Category: Arrowsmith CH]] | ||
[[Category: Bountra | [[Category: Bountra C]] | ||
[[Category: Carpenter | [[Category: Carpenter L]] | ||
[[Category: Chaikuad | [[Category: Chaikuad A]] | ||
[[Category: Edwards A]] | |||
[[Category: Edwards | [[Category: Fedorov O]] | ||
[[Category: Fedorov | [[Category: Filippakopoulos P]] | ||
[[Category: Filippakopoulos | [[Category: Hapka E]] | ||
[[Category: Hapka | [[Category: Knapp S]] | ||
[[Category: Knapp | [[Category: Phillips C]] | ||
[[Category: Phillips | [[Category: Pike ACW]] | ||
[[Category: Pike | [[Category: Rellos P]] | ||
[[Category: Rellos | [[Category: Soundararajan M]] | ||
[[Category: Ugochukwu E]] | |||
[[Category: Soundararajan | [[Category: Vollmar M]] | ||
[[Category: Ugochukwu | [[Category: Wang J]] | ||
[[Category: Vollmar | [[Category: Weigelt J]] | ||
[[Category: Wang | [[Category: Von Delft F]] | ||
[[Category: Weigelt | |||
[[Category: | |||
Latest revision as of 11:40, 6 September 2023
Crystal Structure of human Serine/Threonine Kinase 17B (STK17B) in complex with QuercetinCrystal Structure of human Serine/Threonine Kinase 17B (STK17B) in complex with Quercetin
Structural highlights
FunctionST17B_HUMAN Phosphorylates myosin light chains (By similarity). Acts as a positive regulator of apoptosis.[1] 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 PubMedSTK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied "dark" kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1. A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation.,Picado A, Chaikuad A, Wells CI, Shrestha S, Zuercher WJ, Pickett JE, Kwarcinski FE, Sinha P, de Silva CS, Zutshi R, Liu S, Kannan N, Knapp S, Drewry DH, Willson TM J Med Chem. 2020 Dec 10;63(23):14626-14646. doi: 10.1021/acs.jmedchem.0c01174., Epub 2020 Nov 20. PMID:33215924[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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