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| | <StructureSection load='5cen' size='340' side='right'caption='[[5cen]], [[Resolution|resolution]] 1.70Å' scene=''> | | <StructureSection load='5cen' size='340' side='right'caption='[[5cen]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5cen]] 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=5CEN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CEN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5cen]] 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=5CEN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CEN FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ceo|5ceo]], [[5cep|5cep]], [[5ceq|5ceq]]</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]] 1.7Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAP3K12, ZPK ([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=5cen FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cen OCA], [https://pdbe.org/5cen PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cen RCSB], [https://www.ebi.ac.uk/pdbsum/5cen PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cen 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_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </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=5cen FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cen OCA], [http://pdbe.org/5cen PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cen RCSB], [http://www.ebi.ac.uk/pdbsum/5cen PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5cen ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/M3K12_HUMAN M3K12_HUMAN]] May be an activator of the JNK/SAPK pathway. Phosphorylates beta-casein, histone 1 and myelin basic protein in vitro. | + | [https://www.uniprot.org/uniprot/M3K12_HUMAN M3K12_HUMAN] May be an activator of the JNK/SAPK pathway. Phosphorylates beta-casein, histone 1 and myelin basic protein in vitro. |
| | <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 5cen" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5cen" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Mitogen-activated protein kinase kinase kinase|Mitogen-activated protein kinase kinase kinase]] |
| | == 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 kinase]]
| + | [[Category: HARRIS SF]] |
| - | [[Category: HARRIS, S F]] | + | [[Category: YIN J]] |
| - | [[Category: YIN, J]] | + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Transferase]]
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| Structural highlights
Function
M3K12_HUMAN May be an activator of the JNK/SAPK pathway. Phosphorylates beta-casein, histone 1 and myelin basic protein in vitro.
Publication Abstract from PubMed
Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a number of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochemical properties. We also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, we identified inhibitor 11, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.
Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12).,Patel S, Harris SF, Gibbons P, Deshmukh G, Gustafson A, Kellar T, Lin H, Liu X, Liu Y, Liu Y, Ma C, Scearce-Levie K, Ghosh AS, Shin YG, Solanoy H, Wang J, Wang B, Yin J, Siu M, Lewcock JW J Med Chem. 2015 Oct 2. PMID:26431428[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Patel S, Harris SF, Gibbons P, Deshmukh G, Gustafson A, Kellar T, Lin H, Liu X, Liu Y, Liu Y, Ma C, Scearce-Levie K, Ghosh AS, Shin YG, Solanoy H, Wang J, Wang B, Yin J, Siu M, Lewcock JW. Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12). J Med Chem. 2015 Oct 2. PMID:26431428 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01072
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