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4li6

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Revision as of 20:31, 4 August 2016

TANKYRASE-1 Complexed with small molecule inhibitor N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-3-phenyl-N-(thiophen-2-ylmethyl)propanamide

Structural highlights

4li6 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4li7, 4li8
Gene:	TNKS, PARP5A, PARPL, TIN1, TINF1, TNKS1 (HUMAN)
Activity:	NAD(+) ADP-ribosyltransferase, with EC number 2.4.2.30
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TNKS1_HUMAN] Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure based design and LipE based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19 and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic signature of binding, highly favorable physicochemical properties and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.

Identification of NVP-TNKS656 - The Use of Structure Efficiency Relationships to Generate a Highly Potent, Selective and Orally Active Tankyrase Inhibitor.,Shultz MD, Cheung AK, Kirby CA, Firestone B, Fan J, Chen Z, Chin DN, Dipietro L, Fazal A, Feng Y, Fortin PD, Gould T, Lagu B, Lei H, Lenoir F, Majumdar D, Ochala E, Palermo MG, Pham L, Pu M, Smith T, Stams T, Tomlinson R, Toure BB, Visser M, Wang R, Waters NJ, Shao W J Med Chem. 2013 Jul 11. PMID:23844574^[7]

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

References

↑ Chi NW, Lodish HF. Tankyrase is a golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles. J Biol Chem. 2000 Dec 8;275(49):38437-44. PMID:10988299 doi:10.1074/jbc.M007635200
↑ Cook BD, Dynek JN, Chang W, Shostak G, Smith S. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol. 2002 Jan;22(1):332-42. PMID:11739745
↑ Chang W, Dynek JN, Smith S. NuMA is a major acceptor of poly(ADP-ribosyl)ation by tankyrase 1 in mitosis. Biochem J. 2005 Oct 15;391(Pt 2):177-84. PMID:16076287 doi:10.1042/BJ20050885
↑ Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S, Hild M, Shi X, Wilson CJ, Mickanin C, Myer V, Fazal A, Tomlinson R, Serluca F, Shao W, Cheng H, Shultz M, Rau C, Schirle M, Schlegl J, Ghidelli S, Fawell S, Lu C, Curtis D, Kirschner MW, Lengauer C, Finan PM, Tallarico JA, Bouwmeester T, Porter JA, Bauer A, Cong F. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 2009 Oct 1;461(7264):614-20. doi: 10.1038/nature08356. Epub 2009 Sep 16. PMID:19759537 doi:10.1038/nature08356
↑ Zhang Y, Liu S, Mickanin C, Feng Y, Charlat O, Michaud GA, Schirle M, Shi X, Hild M, Bauer A, Myer VE, Finan PM, Porter JA, Huang SM, Cong F. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat Cell Biol. 2011 May;13(5):623-9. doi: 10.1038/ncb2222. Epub 2011 Apr 10. PMID:21478859 doi:10.1038/ncb2222
↑ Ozaki Y, Matsui H, Asou H, Nagamachi A, Aki D, Honda H, Yasunaga S, Takihara Y, Yamamoto T, Izumi S, Ohsugi M, Inaba T. Poly-ADP ribosylation of Miki by tankyrase-1 promotes centrosome maturation. Mol Cell. 2012 Sep 14;47(5):694-706. doi: 10.1016/j.molcel.2012.06.033. Epub 2012, Aug 2. PMID:22864114 doi:10.1016/j.molcel.2012.06.033
↑ Shultz MD, Cheung AK, Kirby CA, Firestone B, Fan J, Chen Z, Chin DN, Dipietro L, Fazal A, Feng Y, Fortin PD, Gould T, Lagu B, Lei H, Lenoir F, Majumdar D, Ochala E, Palermo MG, Pham L, Pu M, Smith T, Stams T, Tomlinson R, Toure BB, Visser M, Wang R, Waters NJ, Shao W. Identification of NVP-TNKS656 - The Use of Structure Efficiency Relationships to Generate a Highly Potent, Selective and Orally Active Tankyrase Inhibitor. J Med Chem. 2013 Jul 11. PMID:23844574 doi:10.1021/jm400807n

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4li6"

Categories: Human | Kirby, C A | Stams, T | Transferase-transferase inhibitor complex

@@ Line 1: / Line 1: @@
 ==TANKYRASE-1 Complexed with small molecule inhibitor N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-3-phenyl-N-(thiophen-2-ylmethyl)propanamide==
 <StructureSection load='4li6' size='340' side='right' caption='[[4li6]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4li6]] 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=4LI6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LI6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4li6]] is a 2 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=4LI6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LI6 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1XO:N-[(4-OXO-3,4-DIHYDROQUINAZOLIN-2-YL)METHYL]-3-PHENYL-N-(THIOPHEN-2-YLMETHYL)PROPANAMIDE'>1XO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4li7|4li7]], [[4li8|4li8]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TNKS, PARP5A, PARPL, TIN1, TINF1, TNKS1 ([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">TNKS, PARP5A, PARPL, TIN1, TINF1, TNKS1 ([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/NAD(+)_ADP-ribosyltransferase NAD(+) ADP-ribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.30 2.4.2.30] </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=4li6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4li6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4li6 RCSB], [http://www.ebi.ac.uk/pdbsum/4li6 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=4li6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4li6 OCA], [http://pdbe.org/4li6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4li6 RCSB], [http://www.ebi.ac.uk/pdbsum/4li6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4li6 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4li6" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 26: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Kirby, C A]]
 [[Category: Stams, T]]
 [[Category: Transferase-transferase inhibitor complex]]

4li6

From Proteopedia

Revision as of 20:31, 4 August 2016

TANKYRASE-1 Complexed with small molecule inhibitor N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-3-phenyl-N-(thiophen-2-ylmethyl)propanamide

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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