3ptg

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{{STRUCTURE_3ptg| PDB=3ptg | SCENE= }}
 
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===Design and Synthesis of a Novel, Orally Efficacious Tri-substituted Thiophene Based JNK Inhibitor===
 
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{{ABSTRACT_PUBMED_21316234}}
 
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==Disease==
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==Design and Synthesis of a Novel, Orally Efficacious Tri-substituted Thiophene Based JNK Inhibitor==
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[[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. [[http://www.uniprot.org/uniprot/JIP1_HUMAN JIP1_HUMAN]] Defects in MAPK8IP1 are a cause of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:[http://omim.org/entry/125853 125853]]. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance.<ref>PMID:10700186</ref>
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<StructureSection load='3ptg' size='340' side='right'caption='[[3ptg]], [[Resolution|resolution]] 2.43&Aring;' scene=''>
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== Structural highlights ==
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==Function==
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<table><tr><td colspan='2'>[[3ptg]] is a 2 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=3PTG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PTG FirstGlance]. <br>
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[[http://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> [[http://www.uniprot.org/uniprot/JIP1_HUMAN JIP1_HUMAN]] The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity). Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response.
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.43&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=932:N-[4-METHYL-3-(1H-1,2,4-TRIAZOL-5-YL)THIOPHEN-2-YL]-2-(2-OXO-3,4-DIHYDROQUINOLIN-1(2H)-YL)ACETAMIDE'>932</scene></td></tr>
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==About this Structure==
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ptg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ptg OCA], [https://pdbe.org/3ptg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ptg RCSB], [https://www.ebi.ac.uk/pdbsum/3ptg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ptg ProSAT]</span></td></tr>
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[[3ptg]] is a 2 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=3PTG OCA].
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/JIP1_HUMAN JIP1_HUMAN] Defects in MAPK8IP1 are a cause of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:[https://omim.org/entry/125853 125853]. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance.<ref>PMID:10700186</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/JIP1_HUMAN JIP1_HUMAN] The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity). Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response.
==See Also==
==See Also==
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*[[Mitogen-activated protein kinase|Mitogen-activated protein kinase]]
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*[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:021316234</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Mitogen-activated protein kinase]]
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[[Category: Large Structures]]
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[[Category: Artis, D R.]]
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[[Category: Artis DR]]
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[[Category: Bard, F.]]
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[[Category: Bard F]]
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[[Category: Bowers, S.]]
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[[Category: Bowers S]]
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[[Category: Brigham, E F.]]
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[[Category: Brigham EF]]
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[[Category: Griswold-Prenner, I.]]
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[[Category: Griswold-Prenner I]]
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[[Category: Hom, R K.]]
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[[Category: Hom RK]]
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[[Category: Konradi, A W.]]
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[[Category: Konradi AW]]
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[[Category: Neitz, J.]]
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[[Category: Neitz J]]
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[[Category: Neitzel, M.]]
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[[Category: Neitzel M]]
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[[Category: Pan, H.]]
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[[Category: Pan H]]
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[[Category: Powell, K.]]
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[[Category: Powell K]]
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[[Category: Probst, G D.]]
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[[Category: Probst GD]]
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[[Category: Quinn, K P.]]
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[[Category: Quinn KP]]
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[[Category: Ruslim, L.]]
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[[Category: Ruslim L]]
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[[Category: Sauer, J.]]
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[[Category: Sauer J]]
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[[Category: Sham, H L.]]
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[[Category: Sham HL]]
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[[Category: Toth, G.]]
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[[Category: Toth G]]
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[[Category: Truong, A P.]]
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[[Category: Truong AP]]
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[[Category: Yao, N.]]
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[[Category: Yao N]]
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[[Category: Yednock, T A.]]
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[[Category: Yednock TA]]
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[[Category: Jnk inhibitor]]
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[[Category: Neurodegeneration]]
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[[Category: Thiophene]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Design and Synthesis of a Novel, Orally Efficacious Tri-substituted Thiophene Based JNK Inhibitor

PDB ID 3ptg

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