7b36: Difference between revisions
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==MST4 in complex with compound G-5555== | ==MST4 in complex with compound G-5555== | ||
<StructureSection load='7b36' size='340' side='right'caption='[[7b36]]' scene=''> | <StructureSection load='7b36' size='340' side='right'caption='[[7b36]], [[Resolution|resolution]] 2.11Å' 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=7B36 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[7b36]] is a 2 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=7B36 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B36 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=59T:8-[(TRANS-5-AMINO-1,3-DIOXAN-2-YL)METHYL]-6-[2-CHLORO-4-(6-METHYLPYRIDIN-2-YL)PHENYL]-2-(METHYLAMINO)PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>59T</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">STK26, MASK, MST4 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://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=7b36 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b36 OCA], [https://pdbe.org/7b36 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b36 RCSB], [https://www.ebi.ac.uk/pdbsum/7b36 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b36 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/STK26_HUMAN STK26_HUMAN]] Mediator of cell growth (PubMed:11641781, PubMed:17360971). Modulates apoptosis (PubMed:11641781, PubMed:17360971). In association with STK24 negatively regulates Golgi reorientation in polarized cell migration upon RHO activation (PubMed:27807006).<ref>PMID:11641781</ref> <ref>PMID:17360971</ref> <ref>PMID:27807006</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Salt-inducible kinases (SIKs) are key metabolic regulators. The imbalance in SIK function is associated with the development of diverse cancers, including breast, gastric, and ovarian cancers. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based p21-activated kinase (PAK) inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets, MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer. | |||
Structure-Based Design of Selective Salt-Inducible Kinase Inhibitors.,Tesch R, Rak M, Raab M, Berger LM, Kronenberger T, Joerger AC, Berger BT, Abdi I, Hanke T, Poso A, Strebhardt K, Sanhaji M, Knapp S J Med Chem. 2021 Jun 24;64(12):8142-8160. doi: 10.1021/acs.jmedchem.0c02144. Epub, 2021 Jun 4. PMID:34086472<ref>PMID:34086472</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7b36" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Joerger | [[Category: Non-specific serine/threonine protein kinase]] | ||
[[Category: Knapp S]] | [[Category: Joerger, A C]] | ||
[[Category: Rak M]] | [[Category: Knapp, S]] | ||
[[Category: Tesch R]] | [[Category: Rak, M]] | ||
[[Category: Structural genomic]] | |||
[[Category: Tesch, R]] | |||
[[Category: Kinase inhibitor]] | |||
[[Category: Sgc]] | |||
[[Category: Sik2 inhibitor]] | |||
[[Category: Structure-based drug design]] | |||
[[Category: Transferase]] | |||