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2zdt

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Revision as of 19:01, 8 February 2016

Crystal Structure of human JNK3 complexed with an isoquinolone inhibitor

Structural highlights

2zdt is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	2zdu
Activity:	Mitogen-activated protein kinase, with EC number 2.7.11.24
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Disease

[MK10_HUMAN] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:606369]. Epileptic encephalopathies of the Lennox-Gastaut group are childhood epileptic disorders characterized by severe psychomotor delay and seizures. Note=A chromosomal aberration involving MAPK10 has been found in a single patient. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation.

Function

[MK10_HUMAN] Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons.^[1]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

3-Metoxycarbonyl isoquinolone derivative 1 has been identified as a potent JNK inhibitor and significantly inhibited cardiac hypertrophy in a rat pressure-overload model. Herein, a series of isoquinolones with an imidazolylmethyl or a pyrazolylmethyl group at the 2-position were designed based on X-ray crystallographic analysis of the complex between the isoquinolone compound and JNK3, as wells as the relationship between compound lipophilicity (logD) and activity in a cell-based assay. The compounds prepared showed potent JNK1 inhibitory activities in a cell-based assay. Among them the isoquinolone derivative possessing 5-[(cyclopropylamino)carbonyl]-1-methyl-1H-pyrazole (16e) exhibited significant anti-hypertrophic activity at doses of more than 1mg/kg (po) in a pressure-overload model.

Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (2).,Asano Y, Kitamura S, Ohra T, Itoh F, Kajino M, Tamura T, Kaneko M, Ikeda S, Igata H, Kawamoto T, Sogabe S, Matsumoto S, Tanaka T, Yamaguchi M, Kimura H, Fukumoto S Bioorg Med Chem. 2008 Apr 15;16(8):4699-714. Epub 2008 Feb 13. PMID:18313930^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Neidhart S, Antonsson B, Gillieron C, Vilbois F, Grenningloh G, Arkinstall S. c-Jun N-terminal kinase-3 (JNK3)/stress-activated protein kinase-beta (SAPKbeta) binds and phosphorylates the neuronal microtubule regulator SCG10. FEBS Lett. 2001 Nov 16;508(2):259-64. PMID:11718727
↑ Asano Y, Kitamura S, Ohra T, Itoh F, Kajino M, Tamura T, Kaneko M, Ikeda S, Igata H, Kawamoto T, Sogabe S, Matsumoto S, Tanaka T, Yamaguchi M, Kimura H, Fukumoto S. Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (2). Bioorg Med Chem. 2008 Apr 15;16(8):4699-714. Epub 2008 Feb 13. PMID:18313930 doi:10.1016/j.bmc.2008.02.028

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2zdt"

@@ Line 2: / Line 2: @@
 <StructureSection load='2zdt' size='340' side='right' caption='[[2zdt]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2zdt]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZDT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ZDT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2zdt]] 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=2ZDT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ZDT FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=46C:4-[(6-CHLORO-1-OXO-4-PHENYL-3-PROPANOYLISOQUINOLIN-2(1H)-YL)METHYL]BENZOIC+ACID'>46C</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2zdu|2zdu]]</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 Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </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=2zdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zdt OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2zdt RCSB], [http://www.ebi.ac.uk/pdbsum/2zdt PDBsum]</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=2zdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zdt OCA], [http://pdbe.org/2zdt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2zdt RCSB], [http://www.ebi.ac.uk/pdbsum/2zdt PDBsum]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 20: @@
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2zdt ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 30: / Line 30: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2zdt" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 37: / Line 38: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Mitogen-activated protein kinase]]
 [[Category: Asano, Y]]

2zdt

From Proteopedia

Revision as of 19:01, 8 February 2016

Crystal Structure of human JNK3 complexed with an isoquinolone inhibitor

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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