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==Biochemical, Cellular and Structural Characterization of Novel ERK3 Inhibitors== | ==Biochemical, Cellular and Structural Characterization of Novel ERK3 Inhibitors== | ||
<StructureSection load='6yll' size='340' side='right'caption='[[6yll]]' scene=''> | <StructureSection load='6yll' size='340' side='right'caption='[[6yll]], [[Resolution|resolution]] 2.89Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YLL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YLL FirstGlance]. <br> | <table><tr><td colspan='2'>[[6yll]] is a 2 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=6YLL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YLL FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6yll FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yll OCA], [http://pdbe.org/6yll PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yll RCSB], [http://www.ebi.ac.uk/pdbsum/6yll PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yll ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OYB:~{N}4-[3-(4-methoxyphenyl)-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]cyclohexane-1,4-diamine'>OYB</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAPK6, ERK3, PRKM6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6yll FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yll OCA], [http://pdbe.org/6yll PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yll RCSB], [http://www.ebi.ac.uk/pdbsum/6yll PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yll ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/MK06_HUMAN MK06_HUMAN]] Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK3/MAPK6 is phosphorylated at Ser-189 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6. May promote entry in the cell cycle (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Triazolo[4,5-d]pyrimidin-5-amines were identified from kinase selectivity screening as novel ERK3 inhibitors with sub-100 nanomolar potencies in a biochemical assay using MK5 as substrate and with an attractive kinase selectivity profile. ERK3 crystal structures clarified the inhibitor binding mode in the ATP pocket with impact on A-loop, GC-loop and alphaC-helix conformations suggesting a potential structural link towards MK5 interaction via the FHIEDE motif. The inhibitors also showed sub-100 nM potencies in a cellular ERK3 NanoBRET assay and with excellent correlation to the biochemical IC50s. This novel series provides valuable tool compounds to further investigate the biological function and activation mechanism of ERK3. | |||
Biochemical, cellular and structural characterization of novel and selective ERK3 inhibitors.,Gradler U, Busch M, Leuthner B, Raba M, Burgdorf L, Lehmann M, Linde N, Esdar C Bioorg Med Chem Lett. 2020 Sep 11;30(22):127551. doi: 10.1016/j.bmcl.2020.127551. PMID:32927028<ref>PMID:32927028</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6yll" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Graedler U]] | [[Category: Mitogen-activated protein kinase]] | ||
[[Category: Graedler, U]] | |||
[[Category: Erk3]] | |||
[[Category: Inhibitor]] | |||
[[Category: Transferase]] | |||
Revision as of 10:50, 30 September 2020
Biochemical, Cellular and Structural Characterization of Novel ERK3 InhibitorsBiochemical, Cellular and Structural Characterization of Novel ERK3 Inhibitors
Structural highlights
Function[MK06_HUMAN] Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK3/MAPK6 is phosphorylated at Ser-189 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6. May promote entry in the cell cycle (By similarity). Publication Abstract from PubMedTriazolo[4,5-d]pyrimidin-5-amines were identified from kinase selectivity screening as novel ERK3 inhibitors with sub-100 nanomolar potencies in a biochemical assay using MK5 as substrate and with an attractive kinase selectivity profile. ERK3 crystal structures clarified the inhibitor binding mode in the ATP pocket with impact on A-loop, GC-loop and alphaC-helix conformations suggesting a potential structural link towards MK5 interaction via the FHIEDE motif. The inhibitors also showed sub-100 nM potencies in a cellular ERK3 NanoBRET assay and with excellent correlation to the biochemical IC50s. This novel series provides valuable tool compounds to further investigate the biological function and activation mechanism of ERK3. Biochemical, cellular and structural characterization of novel and selective ERK3 inhibitors.,Gradler U, Busch M, Leuthner B, Raba M, Burgdorf L, Lehmann M, Linde N, Esdar C Bioorg Med Chem Lett. 2020 Sep 11;30(22):127551. doi: 10.1016/j.bmcl.2020.127551. PMID:32927028[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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