4l53

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{{STRUCTURE_4l53| PDB=4l53 | SCENE= }}
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==Crystal Structure of (1R,4R)-4-{4-[7-amino-2-(1,2,3-benzothiadiazol-7-yl)-3-chlorofuro[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}cyclohexan-1-ol bound to TAK1-TAB1==
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===Crystal Structure of (1R,4R)-4-{4-[7-amino-2-(1,2,3-benzothiadiazol-7-yl)-3-chlorofuro[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}cyclohexan-1-ol bound to TAK1-TAB1===
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<StructureSection load='4l53' size='340' side='right' caption='[[4l53]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
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{{ABSTRACT_PUBMED_23856049}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4l53]] is a 1 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=4L53 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4L53 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1UO:TRANS-4-{4-[7-AMINO-2-(1,2,3-BENZOTHIADIAZOL-7-YL)-3-CHLOROFURO[2,3-C]PYRIDIN-4-YL]-1H-PYRAZOL-1-YL}CYCLOHEXANOL'>1UO</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4l3p|4l3p]], [[4l52|4l52]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAP3K7, TAK1, MAP3K7IP1, TAB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4l53 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l53 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4l53 RCSB], [http://www.ebi.ac.uk/pdbsum/4l53 PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer.
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==Function==
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Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: Optimization of kinase selectivity and pharmacokinetics.,Hornberger KR, Chen X, Crew AP, Kleinberg A, Ma L, Mulvihill MJ, Wang J, Wilde VL, Albertella M, Bittner M, Cooke A, Kadhim S, Kahler J, Maresca P, May E, Meyn P, Romashko D, Tokar B, Turton R Bioorg Med Chem Lett. 2013 Aug 15;23(16):4511-6. doi: 10.1016/j.bmcl.2013.06.054., Epub 2013 Jun 27. PMID:23856049<ref>PMID:23856049</ref>
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[[http://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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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4l53]] is a 1 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=4L53 OCA].
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</div>
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:023856049</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Mitogen-activated protein kinase kinase kinase]]
[[Category: Mitogen-activated protein kinase kinase kinase]]
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[[Category: Crew, A P.]]
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[[Category: Crew, A P]]
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[[Category: Hornberger, K R.]]
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[[Category: Hornberger, K R]]
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[[Category: Jestel, A.]]
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[[Category: Jestel, A]]
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[[Category: Maskos, K.]]
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[[Category: Maskos, K]]
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[[Category: Moertl, M.]]
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[[Category: Moertl, M]]
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[[Category: Wang, J.]]
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[[Category: Wang, J]]
[[Category: Tak1 kinase]]
[[Category: Tak1 kinase]]
[[Category: Transferase-transferase inhibitor complex]]
[[Category: Transferase-transferase inhibitor complex]]

Revision as of 15:31, 21 December 2014

Crystal Structure of (1R,4R)-4-{4-[7-amino-2-(1,2,3-benzothiadiazol-7-yl)-3-chlorofuro[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}cyclohexan-1-ol bound to TAK1-TAB1

4l53, resolution 2.55Å

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