View source for 3tti


==Crystal Structure of JNK3 complexed with CC-930, an orally active anti-fibrotic JNK inhibitor==
<StructureSection load='3tti' size='340' side='right'caption='[[3tti]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3tti]] 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=3TTI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TTI FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KBI:TRANS-4-({9-[(3S)-TETRAHYDROFURAN-3-YL]-8-[(2,4,6-TRIFLUOROPHENYL)AMINO]-9H-PURIN-2-YL}AMINO)CYCLOHEXANOL'>KBI</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3ttj|3ttj]]</div></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">JNK3, JNK3A, MAPK10, PRKM10 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3tti FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tti OCA], [https://pdbe.org/3tti PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tti RCSB], [https://www.ebi.ac.uk/pdbsum/3tti PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tti ProSAT]</span></td></tr>
</table>
== 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 ==
[[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 ==
In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.

Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor.,Plantevin Krenitsky V, Nadolny L, Delgado M, Ayala L, Clareen SS, Hilgraf R, Albers R, Hegde S, D'Sidocky N, Sapienza J, Wright J, McCarrick M, Bahmanyar S, Chamberlain P, Delker SL, Muir J, Giegel D, Xu L, Celeridad M, Lachowitzer J, Bennett B, Moghaddam M, Khatsenko O, Katz J, Fan R, Bai A, Tang Y, Shirley MA, Benish B, Bodine T, Blease K, Raymon H, Cathers BE, Satoh Y Bioorg Med Chem Lett. 2012 Feb 1;22(3):1433-8. Epub 2011 Dec 10. PMID:22244937<ref>PMID:22244937</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3tti" style="background-color:#fffaf0;"></div>

==See Also==
*[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Mitogen-activated protein kinase]]
[[Category: Albers, R]]
[[Category: Ayala, L]]
[[Category: Bahmanyar, S]]
[[Category: Bai, A]]
[[Category: Benish, B]]
[[Category: Bennett, B]]
[[Category: Blease, K]]
[[Category: Bodine, T]]
[[Category: Cathers, B E]]
[[Category: Celeridad, M]]
[[Category: Chamberlain, P]]
[[Category: Clareen, S]]
[[Category: Delgado, M]]
[[Category: Delker, S L]]
[[Category: Fan, R]]
[[Category: Giegel, D]]
[[Category: Hegde, S]]
[[Category: Hilgraf, R]]
[[Category: Katz, J]]
[[Category: Khatsenko, O]]
[[Category: Lachowitzer, J]]
[[Category: McCarrick, M]]
[[Category: Moghaddam, M]]
[[Category: Muir, J]]
[[Category: Nadolny, L]]
[[Category: Plantevin-Krenitsky, V]]
[[Category: Raymon, H]]
[[Category: Sapienza, J]]
[[Category: Satoh, Y]]
[[Category: Shirley, M A]]
[[Category: Sidocky, N D]]
[[Category: Tang, Y]]
[[Category: Wright, J]]
[[Category: Xu, L]]
[[Category: Jnk3]]
[[Category: Kinase]]
[[Category: Mitogen-activated protein kinase 10]]
[[Category: Protein kinase inhibitor]]
[[Category: Transferase-transferase inhibitor complex]]