4y5h: Difference between revisions
No edit summary |
No edit summary |
||
| Line 3: | Line 3: | ||
<StructureSection load='4y5h' size='340' side='right'caption='[[4y5h]], [[Resolution|resolution]] 2.06Å' scene=''> | <StructureSection load='4y5h' size='340' side='right'caption='[[4y5h]], [[Resolution|resolution]] 2.06Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4y5h]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4y5h]] 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=4Y5H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y5H FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=519:1-(TRANS-4-{[7-OXO-8-(PROPAN-2-YL)-7,8-DIHYDROPYRIDO[2,3-D]PYRIMIDIN-2-YL]AMINO}CYCLOHEXYL)-3-PROPAN-2-YLUREA'>519</scene | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=519:1-(TRANS-4-{[7-OXO-8-(PROPAN-2-YL)-7,8-DIHYDROPYRIDO[2,3-D]PYRIMIDIN-2-YL]AMINO}CYCLOHEXYL)-3-PROPAN-2-YLUREA'>519</scene></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=4y5h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y5h OCA], [https://pdbe.org/4y5h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y5h RCSB], [https://www.ebi.ac.uk/pdbsum/4y5h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y5h ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [https://www.uniprot.org/uniprot/MK10_HUMAN MK10_HUMAN] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:[https://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. | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/MK10_HUMAN 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.<ref>PMID:11718727</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 25: | Line 22: | ||
==See Also== | ==See Also== | ||
*[[Mitogen-activated protein kinase|Mitogen-activated protein kinase]] | *[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Park H]] | |||
[[Category: Park | |||
Revision as of 10:59, 3 May 2023
Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) inhibitorsPyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) inhibitors
Structural highlights
DiseaseMK10_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. FunctionMK10_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 PubMedA novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure-activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC50 = 15 nM), had high selectivity against p38 (IC50 > 10 muM), had high potency in functional cell based assays, and had high stability in human liver microsome (t 1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 A. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition. Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors.,Zheng K, Park CM, Iqbal S, Hernandez P, Park H, LoGrasso PV, Feng Y ACS Med Chem Lett. 2015 Mar 2;6(4):413-8. doi: 10.1021/ml500474d. eCollection, 2015 Apr 9. PMID:25893042[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||