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3fhr

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{{STRUCTURE_3fhr| PDB=3fhr | SCENE= }}
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==High resolution crystal structure of mitogen-activated protein kinase-activated protein kinase 3 (MK3)-inhibitor complex==
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===High resolution crystal structure of mitogen-activated protein kinase-activated protein kinase 3 (MK3)-inhibitor complex===
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<StructureSection load='3fhr' size='340' side='right' caption='[[3fhr]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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{{ABSTRACT_PUBMED_19937655}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3fhr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FHR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3FHR FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=P4O:2-(2-QUINOLIN-3-YLPYRIDIN-4-YL)-1,5,6,7-TETRAHYDRO-4H-PYRROLO[3,2-C]PYRIDIN-4-ONE'>P4O</scene></td></tr>
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<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>
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<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=3fhr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fhr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3fhr RCSB], [http://www.ebi.ac.uk/pdbsum/3fhr PDBsum]</span></td></tr>
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</table>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fh/3fhr_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The Mapkap kinases 2 and 3 (MK2 and MK3) have been implicated in intracellular signalling pathways leading to the production of the pro-inflammatory cytokine tumor necrosis factor alpha. MK2 has been pursued by the biopharmaceutical industry for many years for the development of a small molecule anti-inflammatory treatment and drug-like inhibitors have been described. The development of some of these compounds, however, has been slowed by the absence of a high-resolution crystal structure of MK2. Herein we present a high-resolution (1.9 A) crystal structure of the highly homologous MK3 in complex with a pharmaceutical lead compound. While all of the canonical features of Ser/Thr kinases in general and MK2 in particular are recapitulated in MK3, the detailed analysis of the binding interaction of the drug-like ligand within the adenine binding pocket allows relevant conclusions to be drawn for the further design of potent and selective drug candidates.
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==Function==
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High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand.,Cheng R, Felicetti B, Palan S, Toogood-Johnson I, Scheich C, Barker J, Whittaker M, Hesterkamp T Protein Sci. 2009 Nov 20. PMID:19937655<ref>PMID:19937655</ref>
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[[http://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>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3fhr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FHR OCA].
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</div>
==See Also==
==See Also==
*[[Mitogen-activated protein kinase|Mitogen-activated protein kinase]]
*[[Mitogen-activated protein kinase|Mitogen-activated protein kinase]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:019937655</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Human]]
[[Category: Human]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Barker, J.]]
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[[Category: Barker, J]]
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[[Category: Cheng, R K.Y.]]
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[[Category: Cheng, R K.Y]]
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[[Category: Felicetti, B.]]
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[[Category: Felicetti, B]]
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[[Category: Hesterkamp, T.]]
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[[Category: Hesterkamp, T]]
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[[Category: Palan, S.]]
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[[Category: Palan, S]]
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[[Category: Whittaker, M.]]
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[[Category: Whittaker, M]]
[[Category: Atp-binding]]
[[Category: Atp-binding]]
[[Category: Kinase]]
[[Category: Kinase]]

Revision as of 17:14, 21 December 2014

High resolution crystal structure of mitogen-activated protein kinase-activated protein kinase 3 (MK3)-inhibitor complex

3fhr, resolution 1.90Å

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