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4l3p

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Revision as of 20:14, 4 August 2016

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

Structural highlights

4l3p is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	MAP3K7, TAK1, MAP3K7IP1, TAB1 (HUMAN)
Activity:	Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

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^[9]

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

References

↑ Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, Shirakabe K, Muro Y, Shibuya H, Matsumoto K, Nishida E, Hagiwara M. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem. 1996 Jun 7;271(23):13675-9. PMID:8663074
↑ Shirakabe K, Yamaguchi K, Shibuya H, Irie K, Matsuda S, Moriguchi T, Gotoh Y, Matsumoto K, Nishida E. TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem. 1997 Mar 28;272(13):8141-4. PMID:9079627
↑ Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K. The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature. 1999 Mar 18;398(6724):252-6. PMID:10094049 doi:10.1038/18465
↑ Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001 Jul 19;412(6844):346-51. PMID:11460167 doi:10.1038/35085597
↑ Edlund S, Bu S, Schuster N, Aspenstrom P, Heuchel R, Heldin NE, ten Dijke P, Heldin CH, Landstrom M. Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3. Mol Biol Cell. 2003 Feb;14(2):529-44. PMID:12589052 doi:10.1091/mbc.02-03-0037
↑ Thiefes A, Wolf A, Doerrie A, Grassl GA, Matsumoto K, Autenrieth I, Bohn E, Sakurai H, Niedenthal R, Resch K, Kracht M. The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway. EMBO Rep. 2006 Aug;7(8):838-44. Epub 2006 Jul 14. PMID:16845370 doi:10.1038/sj.embor.7400754
↑ Huangfu WC, Omori E, Akira S, Matsumoto K, Ninomiya-Tsuji J. Osmotic stress activates the TAK1-JNK pathway while blocking TAK1-mediated NF-kappaB activation: TAO2 regulates TAK1 pathways. J Biol Chem. 2006 Sep 29;281(39):28802-10. Epub 2006 Aug 7. PMID:16893890 doi:10.1074/jbc.M603627200
↑ Pertel T, Hausmann S, Morger D, Zuger S, Guerra J, Lascano J, Reinhard C, Santoni FA, Uchil PD, Chatel L, Bisiaux A, Albert ML, Strambio-De-Castillia C, Mothes W, Pizzato M, Grutter MG, Luban J. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature. 2011 Apr 21;472(7343):361-5. doi: 10.1038/nature09976. PMID:21512573 doi:10.1038/nature09976
↑ 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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4l3p"

@@ Line 1: / Line 1: @@
 ==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=''>
 == 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>
+<table><tr><td colspan='2'>[[4l3p]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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='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 HUMAN])</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>
+<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://pdbe.org/4l3p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4l3p RCSB], [http://www.ebi.ac.uk/pdbsum/4l3p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4l3p ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4l3p" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Mitogen-activated protein kinase kinase kinase]]
 [[Category: Crew, A P]]

4l3p

From Proteopedia

Revision as of 20:14, 4 August 2016

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

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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