7akg: Difference between revisions

Latest revision as of 12:11, 1 February 2024

Crystal structure of STK17B with bound dovitinib

Structural highlights

7akg 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 2.08Å
Ligands:	38O, EDO
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ST17B_HUMAN Phosphorylates myosin light chains (By similarity). Acts as a positive regulator of apoptosis.^[1]

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sanjo H, Kawai T, Akira S. DRAKs, novel serine/threonine kinases related to death-associated protein kinase that trigger apoptosis. J Biol Chem. 1998 Oct 30;273(44):29066-71. PMID:9786912
↑ 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. A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation. J Med Chem. 2020 Dec 10;63(23):14626-14646. doi: 10.1021/acs.jmedchem.0c01174., Epub 2020 Nov 20. PMID:33215924 doi:https://dx.doi.org/10.1021/acs.jmedchem.0c01174

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OCA

[1] Sanjo H, Kawai T, Akira S. DRAKs, novel serine/threonine kinases related to death-associated protein kinase that trigger apoptosis. J Biol Chem. 1998 Oct 30;273(44):29066-71. PMID:9786912

[2] 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. A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation. J Med Chem. 2020 Dec 10;63(23):14626-14646. doi: 10.1021/acs.jmedchem.0c01174., Epub 2020 Nov 20. PMID:33215924 doi:https://dx.doi.org/10.1021/acs.jmedchem.0c01174

[1]

[2]

@@ Line 3: / Line 3: @@
 <StructureSection load='7akg' size='340' side='right'caption='[[7akg]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7akg]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AKG OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7AKG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7akg]] 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=7AKG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AKG FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=38O:4-AMINO-5-FLUORO-3-[5-(4-METHYLPIPERAZIN-1-YL)-1H-BENZIMIDAZOL-2-YL]QUINOLIN-2(1H)-ONE'>38O</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 2.08&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">STK17B, DRAK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=38O:4-AMINO-5-FLUORO-3-[5-(4-METHYLPIPERAZIN-1-YL)-1H-BENZIMIDAZOL-2-YL]QUINOLIN-2(1H)-ONE'>38O</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=7akg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7akg OCA], [https://pdbe.org/7akg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7akg RCSB], [https://www.ebi.ac.uk/pdbsum/7akg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7akg ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7akg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7akg OCA], [http://pdbe.org/7akg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7akg RCSB], [http://www.ebi.ac.uk/pdbsum/7akg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7akg ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 7akg" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Chaikuad A]]
-[[Category: Chaikuad, A]]
+[[Category: Knapp S]]
-[[Category: Knapp, S]]
-[[Category: Structural genomic]]
-[[Category: Inhibitor]]
-[[Category: Kinase]]
-[[Category: Sgc]]
-[[Category: Stk17b]]
-[[Category: Transferase]]

7akg: Difference between revisions

Latest revision as of 12:11, 1 February 2024

Crystal structure of STK17B with bound dovitinib

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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