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| | ==MST3 in complex with SARACATINIB== | | ==MST3 in complex with SARACATINIB== |
| - | <StructureSection load='4qmx' size='340' side='right' caption='[[4qmx]], [[Resolution|resolution]] 1.88Å' scene=''> | + | <StructureSection load='4qmx' size='340' side='right'caption='[[4qmx]], [[Resolution|resolution]] 1.88Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4qmx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QMX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QMX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4qmx]] 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=4QMX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QMX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=H8H:N-(5-CHLORO-1,3-BENZODIOXOL-4-YL)-7-[2-(4-METHYLPIPERAZIN-1-YL)ETHOXY]-5-(TETRAHYDRO-2H-PYRAN-4-YLOXY)QUINAZOLIN-4-AMINE'>H8H</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]] 1.882Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H8H:N-(5-CHLORO-1,3-BENZODIOXOL-4-YL)-7-[2-(4-METHYLPIPERAZIN-1-YL)ETHOXY]-5-(TETRAHYDRO-2H-PYRAN-4-YLOXY)QUINAZOLIN-4-AMINE'>H8H</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4qml|4qml]], [[4qmm|4qmm]], [[4qmn|4qmn]], [[4qmo|4qmo]], [[4qmp|4qmp]], [[4qmq|4qmq]], [[4qmr|4qmr]], [[4qms|4qms]], [[4qmt|4qmt]], [[4qmv|4qmv]], [[4qmw|4qmw]], [[4qmz|4qmz]]</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=4qmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qmx OCA], [https://pdbe.org/4qmx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qmx RCSB], [https://www.ebi.ac.uk/pdbsum/4qmx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qmx ProSAT]</span></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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qmx OCA], [http://pdbe.org/4qmx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qmx RCSB], [http://www.ebi.ac.uk/pdbsum/4qmx PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/STK24_HUMAN STK24_HUMAN]] Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress-induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase-independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. Regulates cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12. May act as a key regulator of axon regeneration in the optic nerve and radial nerve.<ref>PMID:16314523</ref> <ref>PMID:17046825</ref> <ref>PMID:19604147</ref> <ref>PMID:19855390</ref> <ref>PMID:19782762</ref> | + | [https://www.uniprot.org/uniprot/STK24_HUMAN STK24_HUMAN] Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress-induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase-independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. Regulates cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12. May act as a key regulator of axon regeneration in the optic nerve and radial nerve.<ref>PMID:16314523</ref> <ref>PMID:17046825</ref> <ref>PMID:19604147</ref> <ref>PMID:19855390</ref> <ref>PMID:19782762</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4qmx" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4qmx" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Olesen, S H]] | + | [[Category: Large Structures]] |
| - | [[Category: Schonbrunn, E]] | + | [[Category: Olesen SH]] |
| - | [[Category: Watts, C]] | + | [[Category: Schonbrunn E]] |
| - | [[Category: Zhu, J Y]] | + | [[Category: Watts C]] |
| - | [[Category: Atp-binding]]
| + | [[Category: Zhu J-Y]] |
| - | [[Category: Mst3]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Phosphoprotein]]
| + | |
| - | [[Category: Protein kinase]]
| + | |
| - | [[Category: Serine/threonine-transferase]]
| + | |
| - | [[Category: Sterile 20-like kinase]]
| + | |
| - | [[Category: Stk24]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
STK24_HUMAN Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress-induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase-independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. Regulates cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12. May act as a key regulator of axon regeneration in the optic nerve and radial nerve.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Increasing evidence suggests key roles for members of the mammalian Sterile20-like (MST) family of kinases in many aspects of biology. MST3 is a member of the STRIPAK complex, the deregulation of which has recently been associated with cancer cell migration and metastasis. Targeting MST3 with small-molecule inhibitors may be beneficial for the treatment of certain cancers, but little information exists on the potential of kinase inhibitor scaffolds to engage with MST3. In this study we screened MST3 against a library of 277 kinase inhibitors using differential scanning fluorimetry and confirmed 14 previously unknown MST3 inhibitors by X-ray crystallography. These compounds, of which eight are in clinical trials or FDA approved, comprise nine distinct chemical scaffolds that inhibit MST3 enzymatic activity with IC50 values between 0.003 and 23 mum. The structure-activity relationships explain the differential inhibitory activity of these compounds against MST3 and the structural basis for high binding potential, the information of which may serve as a framework for the rational design of MST3-selective inhibitors as potential therapeutics and to interrogate the function of this enzyme in diseased cells.
Discovery of Diverse Small-Molecule Inhibitors of Mammalian Sterile20-like Kinase 3 (MST3).,Olesen SH, Zhu JY, Martin MP, Schonbrunn E ChemMedChem. 2016 Jun 6;11(11):1137-44. doi: 10.1002/cmdc.201600115. Epub 2016, May 2. PMID:27135311[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Stegert MR, Hergovich A, Tamaskovic R, Bichsel SJ, Hemmings BA. Regulation of NDR protein kinase by hydrophobic motif phosphorylation mediated by the mammalian Ste20-like kinase MST3. Mol Cell Biol. 2005 Dec;25(24):11019-29. PMID:16314523 doi:10.1128/MCB.25.24.11019-11029.2005
- ↑ Lu TJ, Lai WY, Huang CY, Hsieh WJ, Yu JS, Hsieh YJ, Chang WT, Leu TH, Chang WC, Chuang WJ, Tang MJ, Chen TY, Lu TL, Lai MD. Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (MST3) involves paxillin and protein-tyrosine phosphatase-PEST. J Biol Chem. 2006 Dec 15;281(50):38405-17. Epub 2006 Oct 17. PMID:17046825 doi:10.1074/jbc.M605035200
- ↑ Chen CB, Ng JK, Choo PH, Wu W, Porter AG. Mammalian sterile 20-like kinase 3 (MST3) mediates oxidative-stress-induced cell death by modulating JNK activation. Biosci Rep. 2009 Sep 16;29(6):405-15. doi: 10.1042/BSR20090096. PMID:19604147 doi:10.1042/BSR20090096
- ↑ Lorber B, Howe ML, Benowitz LI, Irwin N. Mst3b, an Ste20-like kinase, regulates axon regeneration in mature CNS and PNS pathways. Nat Neurosci. 2009 Nov;12(11):1407-14. doi: 10.1038/nn.2414. Epub 2009 Oct 25. PMID:19855390 doi:10.1038/nn.2414
- ↑ Lin CY, Wu HY, Wang PL, Yuan CJ. Mammalian Ste20-like protein kinase 3 induces a caspase-independent apoptotic pathway. Int J Biochem Cell Biol. 2010 Jan;42(1):98-105. doi:, 10.1016/j.biocel.2009.09.012. Epub 2009 Sep 25. PMID:19782762 doi:10.1016/j.biocel.2009.09.012
- ↑ Olesen SH, Zhu JY, Martin MP, Schonbrunn E. Discovery of Diverse Small-Molecule Inhibitors of Mammalian Sterile20-like Kinase 3 (MST3). ChemMedChem. 2016 Jun 6;11(11):1137-44. doi: 10.1002/cmdc.201600115. Epub 2016, May 2. PMID:27135311 doi:http://dx.doi.org/10.1002/cmdc.201600115
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