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==DLK in complex with inhibitor 2-((6-(3,3-difluoropyrrolidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-yl)amino)isonicotinonitrile==
==DLK in complex with inhibitor 2-((6-(3,3-difluoropyrrolidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-yl)amino)isonicotinonitrile==
<StructureSection load='5ceo' size='340' side='right' caption='[[5ceo]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
<StructureSection load='5ceo' size='340' side='right'caption='[[5ceo]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5ceo]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CEO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CEO FirstGlance]. <br>
<table><tr><td colspan='2'>[[5ceo]] 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=5CEO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CEO FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=50D:2-[[6-[3,3-BIS(FLUORANYL)PYRROLIDIN-1-YL]-4-[1-(OXETAN-3-YL)PIPERIDIN-4-YL]PYRIDIN-2-YL]AMINO]PYRIDINE-4-CARBONITRILE'>50D</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]] 2.28&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5cen|5cen]], [[5cep|5cep]], [[5ceq|5ceq]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=50D:2-[[6-[3,3-BIS(FLUORANYL)PYRROLIDIN-1-YL]-4-[1-(OXETAN-3-YL)PIPERIDIN-4-YL]PYRIDIN-2-YL]AMINO]PYRIDINE-4-CARBONITRILE'>50D</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5ceo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ceo OCA], [https://pdbe.org/5ceo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ceo RCSB], [https://www.ebi.ac.uk/pdbsum/5ceo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ceo ProSAT]</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=5ceo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ceo OCA], [http://pdbe.org/5ceo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ceo RCSB], [http://www.ebi.ac.uk/pdbsum/5ceo PDBsum]</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;">
== 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<ref>PMID:26431428</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[Mitogen-activated protein kinase kinase kinase|Mitogen-activated protein kinase kinase kinase]]
<div class="pdbe-citations 5ceo" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Mitogen-activated protein kinase kinase kinase]]
[[Category: Homo sapiens]]
[[Category: HARRIS, S F]]
[[Category: Large Structures]]
[[Category: YIN, J]]
[[Category: HARRIS SF]]
[[Category: Kinase]]
[[Category: YIN J]]
[[Category: Transferase-transferase inhibitor complex]]

Latest revision as of 12:20, 6 March 2024

DLK in complex with inhibitor 2-((6-(3,3-difluoropyrrolidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-yl)amino)isonicotinonitrile

5ceo, resolution 2.28Å

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