7b36: Difference between revisions
New page: '''Unreleased structure''' The entry 7b36 is ON HOLD Authors: Tesch, R., Rak, M., Joerger, A.C., Knapp, S., Structural Genomics Consortium (SGC) Description: MST4 in complex with compo... |
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The | ==MST4 in complex with compound G-5555== | ||
<StructureSection load='7b36' size='340' side='right'caption='[[7b36]], [[Resolution|resolution]] 2.11Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7b36]] 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=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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1068108Å</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='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> | |||
== 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> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7b36" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Knapp | ==See Also== | ||
[[Category: | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Joerger AC]] | |||
[[Category: Knapp S]] | |||
[[Category: Rak M]] | |||
[[Category: Tesch R]] | |||
Latest revision as of 15:21, 1 February 2024
MST4 in complex with compound G-5555MST4 in complex with compound G-5555
Structural highlights
FunctionSTK26_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).[1] [2] [3] Publication Abstract from PubMedSalt-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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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