7aqb: Difference between revisions
m Protected "7aqb" [edit=sysop:move=sysop] |
No edit summary |
||
| (One intermediate revision by the same user not shown) | |||
| Line 1: | Line 1: | ||
The entry | ==Crystal structure of human mitogen activated protein kinase 6 (MAPK6)== | ||
<StructureSection load='7aqb' size='340' side='right'caption='[[7aqb]], [[Resolution|resolution]] 2.25Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7aqb]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=2i6l 2i6l]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AQB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AQB 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=7aqb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aqb OCA], [https://pdbe.org/7aqb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aqb RCSB], [https://www.ebi.ac.uk/pdbsum/7aqb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aqb ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://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 == | |||
Extracellular signal-regulated kinase 3 (ERK3), known also as mitogen-activated protein kinase 6 (MAPK6), is an atypical member of MAPK kinase family, which has been poorly studied. Little is known regarding its function in biological processes, yet this atypical kinase has been suggested to play important roles in the migration and invasiveness of certain cancers. The lack of tools, such as a selective inhibitor, hampers the study of ERK3 biology. Here, we report the crystal structure of the kinase domain of this atypical MAPK kinase, providing molecular insights into its distinct ATP binding pocket compared to the classical MAPK ERK2, explaining differences in their inhibitor binding properties. Medium-scale small molecule screening identified a number of inhibitors, several of which unexpectedly exhibited remarkably high inhibitory potencies. The crystal structure of CLK1 in complex with CAF052, one of the most potent inhibitors identified for ERK3, revealed typical type-I binding mode of the inhibitor, which by structural comparison could likely be maintained in ERK3. Together with the presented structural insights, these diverse chemical scaffolds displaying both reversible and irreversible modes of action, will serve as a starting point for the development of selective inhibitors for ERK3, which will be beneficial for elucidating the important functions of this understudied kinase. | |||
Crystal Structure and Inhibitor Identifications Reveal Targeting Opportunity for the Atypical MAPK Kinase ERK3.,Schroder M, Filippakopoulos P, Schwalm MP, Ferrer CA, Drewry DH, Knapp S, Chaikuad A Int J Mol Sci. 2020 Oct 26;21(21). pii: ijms21217953. doi: 10.3390/ijms21217953. PMID:33114754<ref>PMID:33114754</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7aqb" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Filippakopoulos | ==See Also== | ||
[[Category: Knapp | *[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]] | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Chaikuad A]] | |||
[[Category: Filippakopoulos P]] | |||
[[Category: Knapp S]] | |||
[[Category: Schroeder M]] | |||
Latest revision as of 15:14, 1 February 2024
Crystal structure of human mitogen activated protein kinase 6 (MAPK6)Crystal structure of human mitogen activated protein kinase 6 (MAPK6)
Structural highlights
FunctionMK06_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 PubMedExtracellular signal-regulated kinase 3 (ERK3), known also as mitogen-activated protein kinase 6 (MAPK6), is an atypical member of MAPK kinase family, which has been poorly studied. Little is known regarding its function in biological processes, yet this atypical kinase has been suggested to play important roles in the migration and invasiveness of certain cancers. The lack of tools, such as a selective inhibitor, hampers the study of ERK3 biology. Here, we report the crystal structure of the kinase domain of this atypical MAPK kinase, providing molecular insights into its distinct ATP binding pocket compared to the classical MAPK ERK2, explaining differences in their inhibitor binding properties. Medium-scale small molecule screening identified a number of inhibitors, several of which unexpectedly exhibited remarkably high inhibitory potencies. The crystal structure of CLK1 in complex with CAF052, one of the most potent inhibitors identified for ERK3, revealed typical type-I binding mode of the inhibitor, which by structural comparison could likely be maintained in ERK3. Together with the presented structural insights, these diverse chemical scaffolds displaying both reversible and irreversible modes of action, will serve as a starting point for the development of selective inhibitors for ERK3, which will be beneficial for elucidating the important functions of this understudied kinase. Crystal Structure and Inhibitor Identifications Reveal Targeting Opportunity for the Atypical MAPK Kinase ERK3.,Schroder M, Filippakopoulos P, Schwalm MP, Ferrer CA, Drewry DH, Knapp S, Chaikuad A Int J Mol Sci. 2020 Oct 26;21(21). pii: ijms21217953. doi: 10.3390/ijms21217953. PMID:33114754[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||