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6emh

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Crystal structure of JNK3 in complex with a pyridinylimidazole inhibitor

Structural highlights

6emh is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , ,
Gene:	MAPK10, JNK3, JNK3A, PRKM10, SAPK1B (HUMAN)
Activity:	Mitogen-activated protein kinase, with EC number 2.7.11.24
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Starting from known p38alpha mitogen-activated protein kinase (MAPK) inhibitors, a series of inhibitors of the c-Jun N-terminal kinase (JNK) 3 was obtained. Altering the substitution pattern of the pyridinylimidazole scaffold proved to be effective in shifting the inhibitory activity from the original target p38alpha MAPK to the closely related JNK3. In particular, a significant improvement for JNK3 selectivity could be achieved by addressing the hydrophobic region I with a small methyl group. Furthermore, additional structural modifications permitted to explore structure-activity relationships. The most potent inhibitor 4-(4-methyl-2-(methylthio)-1H-imidazol-5-yl)-N-(4-morpholinophenyl)pyridin-2-amin e showed an IC50 value for the JNK3 in the low triple digit nanomolar range and its binding mode was confirmed by X-ray crystallography.

Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38alpha Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.,Ansideri F, Macedo JT, Eitel M, El-Gokha A, Zinad DS, Scarpellini C, Kudolo M, Schollmeyer D, Boeckler FM, Blaum BS, Laufer SA, Koch P ACS Omega. 2018 Jul 31;3(7):7809-7831. doi: 10.1021/acsomega.8b00668. Epub 2018, Jul 12. PMID:30087925^[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
↑ Ansideri F, Macedo JT, Eitel M, El-Gokha A, Zinad DS, Scarpellini C, Kudolo M, Schollmeyer D, Boeckler FM, Blaum BS, Laufer SA, Koch P. Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38alpha Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3. ACS Omega. 2018 Jul 31;3(7):7809-7831. doi: 10.1021/acsomega.8b00668. Epub 2018, Jul 12. PMID:30087925 doi:http://dx.doi.org/10.1021/acsomega.8b00668

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6emh"

@@ Line 1: / Line 1: @@
 ==Crystal structure of JNK3 in complex with a pyridinylimidazole inhibitor==
-<StructureSection load='6emh' size='340' side='right' caption='[[6emh]], [[Resolution|resolution]] 1.76&Aring;' scene=''>
+<StructureSection load='6emh' size='340' side='right'caption='[[6emh]], [[Resolution|resolution]] 1.76&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[6emh]] is a 4 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=6EMH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EMH FirstGlance]. <br>
@@ Line 30: / Line 30: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Mitogen-activated protein kinase]]
 [[Category: Blaum, B S]]

6emh

From Proteopedia

Current revision

Crystal structure of JNK3 in complex with a pyridinylimidazole inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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