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7b36

From Proteopedia

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MST4 in complex with compound G-5555

Structural highlights

7b36 is a 2 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 2.1068108Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).^[1] ^[2] ^[3]

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^[4]

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

References

↑ Lin JL, Chen HC, Fang HI, Robinson D, Kung HJ, Shih HM. MST4, a new Ste20-related kinase that mediates cell growth and transformation via modulating ERK pathway. Oncogene. 2001 Oct 4;20(45):6559-69. doi: 10.1038/sj.onc.1204818. PMID:11641781 doi:http://dx.doi.org/10.1038/sj.onc.1204818
↑ Ma X, Zhao H, Shan J, Long F, Chen Y, Chen Y, Zhang Y, Han X, Ma D. PDCD10 interacts with Ste20-related kinase MST4 to promote cell growth and transformation via modulation of the ERK pathway. Mol Biol Cell. 2007 Jun;18(6):1965-78. Epub 2007 Mar 14. PMID:17360971 doi:10.1091/mbc.E06-07-0608
↑ Mardakheh FK, Self A, Marshall CJ. RHO binding to FAM65A regulates Golgi reorientation during cell migration. J Cell Sci. 2016 Dec 15;129(24):4466-4479. doi: 10.1242/jcs.198614. Epub 2016 Nov, 2. PMID:27807006 doi:http://dx.doi.org/10.1242/jcs.198614
↑ 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. Structure-Based Design of Selective Salt-Inducible Kinase Inhibitors. J Med Chem. 2021 Jun 24;64(12):8142-8160. doi: 10.1021/acs.jmedchem.0c02144. Epub, 2021 Jun 4. PMID:34086472 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c02144

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7b36"

@@ Line 3: / Line 3: @@
 <StructureSection load='7b36' size='340' side='right'caption='[[7b36]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
 == Structural highlights ==
-<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>
+<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='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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1068108&#8491;</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='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='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>
 == 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>
+[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 ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 7b36" 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: Joerger AC]]
-[[Category: Joerger, A C]]
+[[Category: Knapp S]]
-[[Category: Knapp, S]]
+[[Category: Rak M]]
-[[Category: Rak, M]]
+[[Category: Tesch R]]
-[[Category: Structural genomic]]
-[[Category: Tesch, R]]
-[[Category: Kinase inhibitor]]
-[[Category: Sgc]]
-[[Category: Sik2 inhibitor]]
-[[Category: Structure-based drug design]]
-[[Category: Transferase]]

7b36

From Proteopedia

Current revision

MST4 in complex with compound G-5555

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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