5jk3

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'''Unreleased structure'''
 
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The entry 5jk3 is ON HOLD until Paper Publication
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==Crystal structure of TL11-128 bound to TAK1-TAB1==
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<StructureSection load='5jk3' size='340' side='right'caption='[[5jk3]], [[Resolution|resolution]] 2.37&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5jk3]] 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=5JK3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JK3 FirstGlance]. <br>
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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]] 2.371&#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=6L4:~{N}-[2-[5-CHLORANYL-2-[(1-METHYLPYRAZOL-4-YL)AMINO]PYRIMIDIN-4-YL]OXYPHENYL]PROP-2-ENAMIDE'>6L4</scene></td></tr>
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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=5jk3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jk3 OCA], [https://pdbe.org/5jk3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jk3 RCSB], [https://www.ebi.ac.uk/pdbsum/5jk3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jk3 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/TAB1_HUMAN TAB1_HUMAN] May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.<ref>PMID:16879102</ref> [https://www.uniprot.org/uniprot/M3K7_HUMAN M3K7_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity.<ref>PMID:8663074</ref> <ref>PMID:9079627</ref> <ref>PMID:10094049</ref> <ref>PMID:11460167</ref> <ref>PMID:12589052</ref> <ref>PMID:16845370</ref> <ref>PMID:16893890</ref> <ref>PMID:21512573</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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TAK1 (transforming growth factor-beta-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the 'DFG-motif' of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds. Lead compounds such as 2 and 10 showed greater than 10-fold biochemical selectivity for TAK1 over the closely related kinases MEK1 and ERK1 which possess an equivalently positioned cysteine residue. These compounds are smaller, more easily synthesized, and exhibit a different spectrum of kinase selectivity relative to previously reported macrocyclic natural product TAK1 inhibitors such as 5Z-7-oxozeanol.
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Authors: Gurbani, D., Westover, K.D.
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Structure-guided development of covalent TAK1 inhibitors.,Tan L, Gurbani D, Weisberg EL, Hunter JC, Li L, Jones DS, Ficarro SB, Mowafy S, Tam CP, Rao S, Du G, Griffin JD, Sorger PK, Marto JA, Westover KD, Gray NS Bioorg Med Chem. 2017 Feb 1;25(3):838-846. doi: 10.1016/j.bmc.2016.11.035. Epub, 2016 Dec 9. PMID:28011204<ref>PMID:28011204</ref>
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Description: Crystal structure of TL11-128 bound to TAK1-TAB1
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Gurbani, D]]
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<div class="pdbe-citations 5jk3" style="background-color:#fffaf0;"></div>
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[[Category: Westover, K.D]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Gurbani D]]
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[[Category: Westover KD]]

Current revision

Crystal structure of TL11-128 bound to TAK1-TAB1

PDB ID 5jk3

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