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New page: '''Unreleased structure''' The entry 3she is ON HOLD Authors: Oubrie, A., kazemier, B. Description: Novel ATP-competitive MK2 inhibitors with potent biochemical and cell-based activity... |
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==Novel ATP-competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series== | |||
<StructureSection load='3she' size='340' side='right'caption='[[3she]], [[Resolution|resolution]] 2.25Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3she]] 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=3SHE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SHE 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]] 2.25Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=I85:N-{4-[(3S)-4-OXO-1,4,5,6-TETRAHYDROSPIRO[PIPERIDINE-3,7-PYRROLO[3,2-C]PYRIDIN]-2-YL]PYRIDIN-2-YL}-3-(TRIFLUOROMETHYL)BENZAMIDE'>I85</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=3she FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3she OCA], [https://pdbe.org/3she PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3she RCSB], [https://www.ebi.ac.uk/pdbsum/3she PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3she ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MAPK3_HUMAN MAPK3_HUMAN] Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression.<ref>PMID:8626550</ref> <ref>PMID:8774846</ref> <ref>PMID:10383393</ref> <ref>PMID:15563468</ref> <ref>PMID:18021073</ref> <ref>PMID:20599781</ref> | |||
==See Also== | |||
*[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Kazemier B]] | |||
[[Category: Oubrie A]] | |||
Latest revision as of 12:50, 1 March 2024
Novel ATP-competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the seriesNovel ATP-competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series
Structural highlights
FunctionMAPK3_HUMAN Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression.[1] [2] [3] [4] [5] [6] See AlsoReferences
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