4tkf

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of human Tankyrase 2 in complex with IWR-1.

Structural highlights

4tkf is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:	, ,
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

The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated beta-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors.

Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2.,Qiu W, Lam R, Voytyuk O, Romanov V, Gordon R, Gebremeskel S, Vodsedalek J, Thompson C, Beletskaya I, Battaile KP, Pai EF, Rottapel R, Chirgadze NY Acta Crystallogr D Biol Crystallogr. 2014 Oct;70(Pt 10):2740-53. doi:, 10.1107/S1399004714017660. Epub 2014 Sep 27. PMID:25286857^[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
↑ Qiu W, Lam R, Voytyuk O, Romanov V, Gordon R, Gebremeskel S, Vodsedalek J, Thompson C, Beletskaya I, Battaile KP, Pai EF, Rottapel R, Chirgadze NY. Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2. Acta Crystallogr D Biol Crystallogr. 2014 Oct;70(Pt 10):2740-53. doi:, 10.1107/S1399004714017660. Epub 2014 Sep 27. PMID:25286857 doi:http://dx.doi.org/10.1107/S1399004714017660

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/4tkf"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 4tkf is ON HOLD
+==Crystal Structure of human Tankyrase 2 in complex with IWR-1.==
+<StructureSection load='4tkf' size='340' side='right'caption='[[4tkf]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4tkf]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TKF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TKF FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=33C:4-[(3AR,4R,7S,7AS)-1,3-DIOXOOCTAHYDRO-2H-4,7-METHANOISOINDOL-2-YL]-N-(QUINOLIN-8-YL)BENZAMIDE'>33C</scene>, <scene name='pdbligand=3AB:3-AMINOBENZAMIDE'>3AB</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4tkf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tkf OCA], [https://pdbe.org/4tkf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tkf RCSB], [https://www.ebi.ac.uk/pdbsum/4tkf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tkf ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/TNKS2_HUMAN 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.<ref>PMID:11802774</ref> <ref>PMID:11739745</ref> <ref>PMID:19759537</ref> <ref>PMID:21478859</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated beta-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors.
-Authors: Qiu, W., Lam, R., Romanov, V., Gordon, R., Gebremeskel, S., Vodsedalek, J., Thompson, C., Beletskaya, I., Battaile, K.P., Pai, E.F., Chirgadze, N.Y.
+Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2.,Qiu W, Lam R, Voytyuk O, Romanov V, Gordon R, Gebremeskel S, Vodsedalek J, Thompson C, Beletskaya I, Battaile KP, Pai EF, Rottapel R, Chirgadze NY Acta Crystallogr D Biol Crystallogr. 2014 Oct;70(Pt 10):2740-53. doi:, 10.1107/S1399004714017660. Epub 2014 Sep 27. PMID:25286857<ref>PMID:25286857</ref>
-Description: Crystal Structure of human Tankyrase 2 in complex with IWR-1.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 4tkf" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Battaile KP]]
+[[Category: Beletskaya I]]
+[[Category: Chirgadze NY]]
+[[Category: Gebremeskel S]]
+[[Category: Gordon R]]
+[[Category: Lam R]]
+[[Category: Pai EF]]
+[[Category: Qiu W]]
+[[Category: Romanov V]]
+[[Category: Thompson C]]
+[[Category: Vodsedalek J]]

4tkf

From Proteopedia

Current revision

Crystal Structure of human Tankyrase 2 in complex with IWR-1.

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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