3rtp: Difference between revisions

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<StructureSection load='3rtp' size='340' side='right'caption='[[3rtp]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
<StructureSection load='3rtp' size='340' side='right'caption='[[3rtp]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3rtp]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RTP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RTP FirstGlance]. <br>
<table><tr><td colspan='2'>[[3rtp]] 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=3RTP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RTP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=34I:N-[4-CYANO-3-(1H-1,2,4-TRIAZOL-5-YL)THIOPHEN-2-YL]-2-(2-OXO-3,4-DIHYDROQUINOLIN-1(2H)-YL)ACETAMIDE'>34I</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]] 2.4&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAPK10, JNK3, JNK3A, PRKM10 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=34I:N-[4-CYANO-3-(1H-1,2,4-TRIAZOL-5-YL)THIOPHEN-2-YL]-2-(2-OXO-3,4-DIHYDROQUINOLIN-1(2H)-YL)ACETAMIDE'>34I</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3rtp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rtp OCA], [https://pdbe.org/3rtp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rtp RCSB], [https://www.ebi.ac.uk/pdbsum/3rtp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rtp ProSAT]</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=3rtp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rtp OCA], [https://pdbe.org/3rtp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rtp RCSB], [https://www.ebi.ac.uk/pdbsum/3rtp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rtp ProSAT]</span></td></tr>
</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.  
[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> 
[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;">
== Publication Abstract from PubMed ==
The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.
 
Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration.,Bowers S, Truong AP, Jeffrey Neitz R, Hom RK, Sealy JM, Probst GD, Quincy D, Peterson B, Chan W, Galemmo RA Jr, Konradi AW, Sham HL, Toth G, Pan H, Lin M, Yao N, Artis DR, Zhang H, Chen L, Dryer M, Samant B, Zmolek W, Wong K, Lorentzen C, Goldbach E, Tonn G, Quinn KP, Sauer JM, Wright S, Powell K, Ruslim L, Ren Z, Bard F, Yednock TA, Griswold-Prenner I Bioorg Med Chem Lett. 2011 Sep 15;21(18):5521-7. doi: 10.1016/j.bmcl.2011.06.100., Epub 2011 Jul 7. PMID:21813278<ref>PMID:21813278</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3rtp" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Mitogen-activated protein kinase]]
[[Category: Artis DR]]
[[Category: Artis, D R]]
[[Category: Bard F]]
[[Category: Bard, F]]
[[Category: Bowers S]]
[[Category: Bowers, S]]
[[Category: Chan W]]
[[Category: Chan, W]]
[[Category: Chen L]]
[[Category: Chen, L]]
[[Category: Dryer M]]
[[Category: Dryer, M]]
[[Category: Galemmo Jr RA]]
[[Category: Galemmo, R A]]
[[Category: Goldbach E]]
[[Category: Goldbach, E]]
[[Category: Griswold-Prenne I]]
[[Category: Griswold-Prenne, I]]
[[Category: Hom RK]]
[[Category: Hom, R K]]
[[Category: Konradi AW]]
[[Category: Konradi, A W]]
[[Category: Lin M]]
[[Category: Lin, M]]
[[Category: Lorentzen C]]
[[Category: Lorentzen, C]]
[[Category: Neitz RJ]]
[[Category: Neitz, R J]]
[[Category: Pan H]]
[[Category: Pan, H]]
[[Category: Peterson B]]
[[Category: Peterson, B]]
[[Category: Powell K]]
[[Category: Powell, K]]
[[Category: Probst GD]]
[[Category: Probst, G D]]
[[Category: Quincy Q]]
[[Category: Quincy, Q]]
[[Category: Quinn KP]]
[[Category: Quinn, K P]]
[[Category: Ren Z]]
[[Category: Ren, Z]]
[[Category: Ruslim L]]
[[Category: Ruslim, L]]
[[Category: Samant B]]
[[Category: Samant, B]]
[[Category: Sauer J]]
[[Category: Sauer, J]]
[[Category: Sealy JM]]
[[Category: Sealy, J M]]
[[Category: Sham HL]]
[[Category: Sham, H L]]
[[Category: Tonn G]]
[[Category: Tonn, G]]
[[Category: Truong AP]]
[[Category: Truong, A P]]
[[Category: Wong K]]
[[Category: Wong, K]]
[[Category: Wright S]]
[[Category: Wright, S]]
[[Category: Yao N]]
[[Category: Yao, N]]
[[Category: Yednock TA]]
[[Category: Yednock, T A]]
[[Category: Zhang H]]
[[Category: Zhang, H]]
[[Category: Zmolek W]]
[[Category: Zmolek, W]]
[[Category: Jnk inhibitor]]
[[Category: Neurodegeneration]]
[[Category: Pharmacokinetic property]]
[[Category: Transferase-transferase inhibitor complex]]

Latest revision as of 12:45, 1 March 2024

Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegenerationDesign and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration

Structural highlights

3rtp 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.
Method:X-ray diffraction, Resolution 2.4Å
Ligands:
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]

See Also

References

  1. ↑ 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

3rtp, resolution 2.40Å

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