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5adq

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Revision as of 07:29, 3 July 2019

Crystal structure of human tankyrase 2 in complex with JW55

Structural highlights

5adq 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:	5adr, 5ads, 5adt
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TNKS2_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 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 poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Tankyrases 1 and 2, the specialized members of the ARTD protein family, are druggable biotargets whose inhibition may have therapeutic potential against cancer, metabolic disease, fibrotic disease, fibrotic wound healing and HSV viral infections. We have previously identified a novel tankyrase inhibitor scaffold, JW55, and showed that it reduces mouse colon adenoma formation in vivo. Here we expanded the scaffold and profiled the selectivity of the compounds against a panel of human ARTDs. The scaffold also enables a fine modulation of selectivity towards either tankyrase 1 or tankyrase 2. In order to get insight about the binding mode of the inhibitors, we solved crystal structures of the compounds in complex with tankyrase 2. The compounds bind to the adenosine pocket of the catalytic domain and cause changes in the protein structure that are modulated by the chemical modifications of the compounds. The structural analysis allows further rational development of this compound class as a potent and selective tankyrase inhibitor.

Development and structural analysis of adenosine site binding tankyrase inhibitors.,Haikarainen T, Waaler J, Ignatev A, Nkizinkiko Y, Venkannagari H, Obaji E, Krauss S, Lehtio L Bioorg Med Chem Lett. 2016 Jan 15;26(2):328-33. doi: 10.1016/j.bmcl.2015.12.018. , Epub 2015 Dec 8. PMID:26706174^[5]

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

References

↑ Sbodio JI, Lodish HF, Chi NW. Tankyrase-2 oligomerizes with tankyrase-1 and binds to both TRF1 (telomere-repeat-binding factor 1) and IRAP (insulin-responsive aminopeptidase). Biochem J. 2002 Feb 1;361(Pt 3):451-9. PMID:11802774
↑ 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
↑ 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
↑ Haikarainen T, Waaler J, Ignatev A, Nkizinkiko Y, Venkannagari H, Obaji E, Krauss S, Lehtio L. Development and structural analysis of adenosine site binding tankyrase inhibitors. Bioorg Med Chem Lett. 2016 Jan 15;26(2):328-33. doi: 10.1016/j.bmcl.2015.12.018. , Epub 2015 Dec 8. PMID:26706174 doi:http://dx.doi.org/10.1016/j.bmcl.2015.12.018

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/5adq"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human tankyrase 2 in complex with JW55==
-<StructureSection load='5adq' size='340' side='right' caption='[[5adq]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+<StructureSection load='5adq' size='340' side='right'caption='[[5adq]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5adq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ADQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ADQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5adq]] 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=5ADQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ADQ FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A95:N-(4-(((4-(4-METHOXYPHENYL)OXAN-4-+YL)METHYL)CARBAMOYL)PHENYL)FURAN-2-CARBOXAMIDE'>A95</scene>, <scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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">[[5adr|5adr]], [[5ads|5ads]], [[5adt|5adt]]</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=5adq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5adq OCA], [http://pdbe.org/5adq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5adq RCSB], [http://www.ebi.ac.uk/pdbsum/5adq 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=5adq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5adq OCA], [http://pdbe.org/5adq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5adq RCSB], [http://www.ebi.ac.uk/pdbsum/5adq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5adq ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 5adq" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Poly (ADP-ribose) polymerase|Poly (ADP-ribose) polymerase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Haikarainen, T]]
 [[Category: Lehtio, L]]

5adq

From Proteopedia

Revision as of 07:29, 3 July 2019

Crystal structure of human tankyrase 2 in complex with JW55

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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