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| | <StructureSection load='6qft' size='340' side='right'caption='[[6qft]], [[Resolution|resolution]] 2.70Å' scene=''> | | <StructureSection load='6qft' size='340' side='right'caption='[[6qft]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6qft]] 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=6QFT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QFT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6qft]] 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=6QFT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QFT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=J0B:1-[(3~{R})-3-(4-azanyl-3-iodanyl-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl]propan-1-one'>J0B</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6qfl|6qfl]], [[6qfr|6qfr]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=J0B:1-[(3~{R})-3-(4-azanyl-3-iodanyl-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl]propan-1-one'>J0B</scene></td></tr> |
| - | <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> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6qft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qft OCA], [https://pdbe.org/6qft PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qft RCSB], [https://www.ebi.ac.uk/pdbsum/6qft PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qft ProSAT]</span></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_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>
| + | |
| - | <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=6qft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qft OCA], [http://pdbe.org/6qft PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qft RCSB], [http://www.ebi.ac.uk/pdbsum/6qft PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qft ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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> [:] | + | [https://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> [:] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6qft" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6qft" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Mitogen-activated protein kinase kinase 3D structures|Mitogen-activated protein kinase kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Mitogen-activated protein kinase kinase]]
| + | [[Category: Mueller MP]] |
| - | [[Category: Mueller, M P]] | + | [[Category: Rauh D]] |
| - | [[Category: Rauh, D]] | + | [[Category: Wolle P]] |
| - | [[Category: Wolle, P]] | + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Mkk7]]
| + | |
| - | [[Category: Protein kinase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
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.[1] [2] [3] [:]
Publication Abstract from PubMed
Pyrazolopyrimidines are well established as covalent inhibitors of protein kinases such as the epidermal growth factor receptor (EGFR) or Bruton's tyrosine kinase (BTK) and we recently described their potential in targeting MKK7. Herein, we report the structure-activity relationship of pyrazolopyrimidine-based MKK7 inhibitors and solved sever-al complex crystal structures to gain insights into their binding mode. In addition, we present two structures of apo-MKK7, exhibiting a DFG-out and an unprecedented DFG-in/Leu-in conformation.
Characterization of Covalent Pyrazolopyrimidine-MKK7 Complexes and Report on a Unique DFG-in/Leu-in Conformation of the Mitogen Activated Protein Kinase Kinase 7 (MKK7).,Wolle P, Engel J, Smith S, Goebel L, Hennes E, Lategahn J, Rauh D J Med Chem. 2019 May 14. doi: 10.1021/acs.jmedchem.9b00472. PMID:31083997[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wu Z, Wu J, Jacinto E, Karin M. Molecular cloning and characterization of human JNKK2, a novel Jun NH2-terminal kinase-specific kinase. Mol Cell Biol. 1997 Dec;17(12):7407-16. PMID:9372971
- ↑ Lu X, Nemoto S, Lin A. Identification of c-Jun NH2-terminal protein kinase (JNK)-activating kinase 2 as an activator of JNK but not p38. J Biol Chem. 1997 Oct 3;272(40):24751-4. PMID:9312068
- ↑ Foltz IN, Gerl RE, Wieler JS, Luckach M, Salmon RA, Schrader JW. Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activated by environmental stresses and physiological stimuli. J Biol Chem. 1998 Apr 10;273(15):9344-51. PMID:9535930
- ↑ Wolle P, Engel J, Smith S, Goebel L, Hennes E, Lategahn J, Rauh D. Characterization of Covalent Pyrazolopyrimidine-MKK7 Complexes and Report on a Unique DFG-in/Leu-in Conformation of the Mitogen Activated Protein Kinase Kinase 7 (MKK7). J Med Chem. 2019 May 14. doi: 10.1021/acs.jmedchem.9b00472. PMID:31083997 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00472
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