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{{STRUCTURE_4l3p|  PDB=4l3p  |  SCENE=  }}
==Crystal Structure of 2-(1-benzothiophen-7-yl)-4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-amine bound to TAK1-TAB1==
===Crystal Structure of 2-(1-benzothiophen-7-yl)-4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-amine bound to TAK1-TAB1===
<StructureSection load='4l3p' size='340' side='right' caption='[[4l3p]], [[Resolution|resolution]] 2.68&Aring;' scene=''>
{{ABSTRACT_PUBMED_23850198}}
== Structural highlights ==
<table><tr><td colspan='2'>[[4l3p]] 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=4L3P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4L3P FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1UH:2-(1-BENZOTHIOPHEN-7-YL)-4-[1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL]FURO[2,3-C]PYRIDIN-7-AMINE'>1UH</scene></td></tr>
<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>
<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>
<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=4l3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l3p OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4l3p RCSB], [http://www.ebi.ac.uk/pdbsum/4l3p PDBsum]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to approximately 10nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization.


==Function==
Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1.,Hornberger KR, Berger DM, Crew AP, Dong H, Kleinberg A, Li AH, Medeiros MR, Mulvihill MJ, Siu K, Tarrant J, Wang J, Weng F, Wilde VL, Albertella M, Bittner M, Cooke A, Gray MJ, Maresca P, May E, Meyn P, Peick W Jr, Romashko D, Tanowitz M, Tokar B Bioorg Med Chem Lett. 2013 Aug 15;23(16):4517-22. doi:, 10.1016/j.bmcl.2013.06.053. Epub 2013 Jun 25. PMID:23850198<ref>PMID:23850198</ref>
[[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>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4l3p]] 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=4L3P OCA].
</div>
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:023850198</ref><references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Mitogen-activated protein kinase kinase kinase]]
[[Category: Mitogen-activated protein kinase kinase kinase]]
[[Category: Crew, A P.]]
[[Category: Crew, A P]]
[[Category: Hornberger, K R.]]
[[Category: Hornberger, K R]]
[[Category: Maskos, K.]]
[[Category: Maskos, K]]
[[Category: Moertl, M.]]
[[Category: Moertl, M]]
[[Category: Steinbacher, S.]]
[[Category: Steinbacher, S]]
[[Category: Wang, J.]]
[[Category: Wang, J]]
[[Category: Transferase-transferase inhibitor complex]]
[[Category: Transferase-transferase inhibitor complex]]

Revision as of 18:11, 21 December 2014

Crystal Structure of 2-(1-benzothiophen-7-yl)-4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-amine bound to TAK1-TAB1Crystal Structure of 2-(1-benzothiophen-7-yl)-4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-amine bound to TAK1-TAB1

Structural highlights

4l3p 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.
Ligands:
Gene:MAP3K7, TAK1, MAP3K7IP1, TAB1 (Homo sapiens)
Activity:Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25
Resources:FirstGlance, OCA, RCSB, PDBsum

Publication Abstract from PubMed

The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to approximately 10nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization.

Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1.,Hornberger KR, Berger DM, Crew AP, Dong H, Kleinberg A, Li AH, Medeiros MR, Mulvihill MJ, Siu K, Tarrant J, Wang J, Weng F, Wilde VL, Albertella M, Bittner M, Cooke A, Gray MJ, Maresca P, May E, Meyn P, Peick W Jr, Romashko D, Tanowitz M, Tokar B Bioorg Med Chem Lett. 2013 Aug 15;23(16):4517-22. doi:, 10.1016/j.bmcl.2013.06.053. Epub 2013 Jun 25. PMID:23850198[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Hornberger KR, Berger DM, Crew AP, Dong H, Kleinberg A, Li AH, Medeiros MR, Mulvihill MJ, Siu K, Tarrant J, Wang J, Weng F, Wilde VL, Albertella M, Bittner M, Cooke A, Gray MJ, Maresca P, May E, Meyn P, Peick W Jr, Romashko D, Tanowitz M, Tokar B. Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1. Bioorg Med Chem Lett. 2013 Aug 15;23(16):4517-22. doi:, 10.1016/j.bmcl.2013.06.053. Epub 2013 Jun 25. PMID:23850198 doi:10.1016/j.bmcl.2013.06.053

4l3p, resolution 2.68Å

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