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1pmn

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Revision as of 07:07, 6 January 2015

Crystal structure of JNK3 in complex with an imidazole-pyrimidine inhibitor

Structural highlights

1pmn is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1pmq, 1pmu, 1pmv
Gene:	MK10_HUMAN (Homo sapiens)
Resources:	FirstGlance, OCA, 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

The c-Jun terminal kinases (JNKs) are members of the mitogen-activated protein (MAP) kinase family and regulate signal transduction in response to environmental stress. Activation of JNK3, a neuronal-specific isoform, has been associated with neurological damage, and as such, JNK3 may represent an attractive target for the treatment of neurological disorders. The MAP kinases share between 50% and 80% sequence identity. In order to obtain efficacious and safe compounds, it is necessary to address the issues of potency and selectivity. We report here four crystal structures of JNK3 in complex with three different classes of inhibitors. These structures provide a clear picture of the interactions that each class of compound made with the kinase. Knowledge of the atomic interactions involved in these diverse binding modes provides a platform for structure-guided modification of these compounds, or the de novo design of novel inhibitors that could satisfy the need for potency and selectivity.

The structure of JNK3 in complex with small molecule inhibitors: structural basis for potency and selectivity.,Scapin G, Patel SB, Lisnock J, Becker JW, LoGrasso PV Chem Biol. 2003 Aug;10(8):705-12. PMID:12954329^[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
↑ Scapin G, Patel SB, Lisnock J, Becker JW, LoGrasso PV. The structure of JNK3 in complex with small molecule inhibitors: structural basis for potency and selectivity. Chem Biol. 2003 Aug;10(8):705-12. PMID:12954329

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/1pmn"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1pmn]] 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=1PMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1PMN FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=984:CYCLOPROPYL-{4-[5-(3,4-DICHLOROPHENYL)-2-[(1-METHYL)-PIPERIDIN]-4-YL-3-PROPYL-3H-IMIDAZOL-4-YL]-PYRIMIDIN-2-YL}AMINE'>984</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=984:CYCLOPROPYL-{4-[5-(3,4-DICHLOROPHENYL)-2-[(1-METHYL)-PIPERIDIN]-4-YL-3-PROPYL-3H-IMIDAZOL-4-YL]-PYRIMIDIN-2-YL}AMINE'>984</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1pmq|1pmq]], [[1pmu|1pmu]], [[1pmv|1pmv]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1pmq|1pmq]], [[1pmu|1pmu]], [[1pmv|1pmv]]</td></tr>
-<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MK10_HUMAN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MK10_HUMAN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1pmn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pmn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1pmn RCSB], [http://www.ebi.ac.uk/pdbsum/1pmn 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=1pmn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pmn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1pmn RCSB], [http://www.ebi.ac.uk/pdbsum/1pmn PDBsum]</span></td></tr>
-<table>
+</table>
 == Disease ==
 [[http://www.uniprot.org/uniprot/MK10_HUMAN MK10_HUMAN]] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:[http://omim.org/entry/606369 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.
@@ Line 38: / Line 38: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Becker, J W.]]
+[[Category: Becker, J W]]
-[[Category: Lisnock, J.]]
+[[Category: Lisnock, J]]
-[[Category: LoGrasso, P V.]]
+[[Category: LoGrasso, P V]]
-[[Category: Patel, S B.]]
+[[Category: Patel, S B]]
-[[Category: Scapin, G.]]
+[[Category: Scapin, G]]
 [[Category: Apoptosis]]
 [[Category: Inhibition]]
 [[Category: Map kinase]]
 [[Category: Transferase]]

1pmn

From Proteopedia

Revision as of 07:07, 6 January 2015

Crystal structure of JNK3 in complex with an imidazole-pyrimidine 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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