6yz4

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==Crystal structure of MKK7 (MAP2K7) with ibrutinib bound at allosteric site==
==Crystal structure of MKK7 (MAP2K7) with ibrutinib bound at allosteric site==
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<StructureSection load='6yz4' size='340' side='right'caption='[[6yz4]]' scene=''>
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<StructureSection load='6yz4' size='340' side='right'caption='[[6yz4]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YZ4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YZ4 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6yz4]] 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=6YZ4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YZ4 FirstGlance]. <br>
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</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=6yz4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yz4 OCA], [http://pdbe.org/6yz4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yz4 RCSB], [http://www.ebi.ac.uk/pdbsum/6yz4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yz4 ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1E8:1-{(3R)-3-[4-AMINO-3-(4-PHENOXYPHENYL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN-1-YL]PIPERIDIN-1-YL}PROP-2-EN-1-ONE'>1E8</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAP2K7, JNKK2, MEK7, MKK7, PRKMK7, SKK4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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/Mitogen-activated_protein_kinase_kinase Mitogen-activated protein kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.2 2.7.12.2] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6yz4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yz4 OCA], [http://pdbe.org/6yz4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yz4 RCSB], [http://www.ebi.ac.uk/pdbsum/6yz4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yz4 ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[[http://www.uniprot.org/uniprot/MP2K7_HUMAN MP2K7_HUMAN]] Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K4/MKK4, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4/MKK4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The monophosphorylation of JNKs on the Thr residue is sufficient to increase JNK activity indicating that MAP2K7/MKK7 is important to trigger JNK activity, while the additional phosphorylation of the Tyr residue by MAP2K4/MKK4 ensures optimal JNK activation. Has a specific role in JNK signal transduction pathway activated by proinflammatory cytokines. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis.<ref>PMID:9372971</ref> <ref>PMID:9312068</ref> <ref>PMID:9535930</ref> [:]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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MKK7 (MEK7) is a key regulator of the JNK stress signaling pathway and targeting MKK7 has been proposed as a chemotherapeutic strategy. Detailed understanding of the MKK7 structure and factors that affect its activity is therefore of critical importance. Here, we present a comprehensive set of MKK7 crystal structures revealing insights into catalytic domain plasticity and the role of the N-terminal regulatory helix, conserved in all MAP2Ks, mediating kinase activation. Crystal structures harboring this regulatory helix revealed typical structural features of active kinase, providing exclusively a first model of the MAP2K active state. A small-molecule screening campaign yielded multiple scaffolds, including type II irreversible inhibitors a binding mode that has not been reported previously. We also observed an unprecedented allosteric pocket located in the N-terminal lobe for the approved drug ibrutinib. Collectively, our structural and functional data expand and provide alternative targeting strategies for this important MAP2K kinase.
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Catalytic Domain Plasticity of MKK7 Reveals Structural Mechanisms of Allosteric Activation and Diverse Targeting Opportunities.,Schroder M, Tan L, Wang J, Liang Y, Gray NS, Knapp S, Chaikuad A Cell Chem Biol. 2020 Aug 4. pii: S2451-9456(20)30287-7. doi:, 10.1016/j.chembiol.2020.07.014. PMID:32783966<ref>PMID:32783966</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6yz4" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Chaikuad A]]
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[[Category: Mitogen-activated protein kinase kinase]]
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[[Category: Knapp S]]
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[[Category: Chaikuad, A]]
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[[Category: Knapp, S]]
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[[Category: Structural genomic]]
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[[Category: Allosteric]]
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[[Category: Jnk signaling]]
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[[Category: Kinase]]
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[[Category: Kinase inhibitor]]
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[[Category: Map2k]]
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[[Category: Map2k7]]
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[[Category: Mek]]
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[[Category: Mek7]]
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[[Category: Mkk7]]
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[[Category: Sgc]]
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[[Category: Transferase]]

Revision as of 07:12, 2 September 2020

Crystal structure of MKK7 (MAP2K7) with ibrutinib bound at allosteric site

PDB ID 6yz4

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