7ce4

From Proteopedia

(Difference between revisions)

Current revision

Tankyrase2 catalytic domain in complex with K-476

Structural highlights

7ce4 is a 2 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 1.5Å
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 Wnt/beta-catenin pathway, which is associated with disease progression, is activated in many cancers. Tankyrase (TNKS) has received attention as a target molecule for Wnt/beta-catenin pathway inhibition. We identified K-476, a novel TNKS inhibitor, a dual pocket binder that binds to both the nicotinamide and ADP-ribose pockets. In a human colon cancer cell line, K-476 specifically and potently inhibited TNKS and led to stabilization of the Axin protein, resulting in Wnt/beta-catenin pathway suppression. Aberrant Wnt/beta-catenin pathway activation was recently reported as a possible mechanism of ineffectiveness in immune checkpoint inhibitor (ICI) treatment. Because the Wnt/beta-catenin pathway activation causes dendritic cell inactivation and suppresses chemokine production, resulting in a paucity of CD8(+) T cells in tumor tissue, which is an important effector of ICIs. Thus, TNKS inhibitors may enhance the efficacy of ICIs. To examine whether K-476 enhances the antitumor effect of anti-PD-L1 antibodies, K-476 was administered orally with an anti-PD-L1 antibody to melanoma-bearing C57BL/6J mice. Although K-476 was ineffective as a monotherapy, it significantly enhanced the antitumor effect in combination with anti-PD-L1 antibody. In mice, intra-tumor infiltration of CD8(+) T cells was increased by combination treatment. K-476 upregulated the chemokine expression (e.g., Ccl3 and Ccl4), which attracted CD8(+) T cells. This was considered to contribute to the increased CD8(+) T cells in the tumor microenvironment. Furthermore, while the potential gastrointestinal toxicity of TNKS inhibitors has been reported, it was not observed at effective doses. Thus, K-476 could be an attractive therapeutic option to enhance the efficacy of ICIs.

The dual pocket binding novel tankyrase inhibitor K-476 enhances the efficacy of immune checkpoint inhibitor by attracting CD8(+) T cells to tumors.,Kinosada H, Okada-Iwasaki R, Kunieda K, Suzuki-Imaizumi M, Takahashi Y, Miyagi H, Suzuki M, Motosawa K, Watanabe M, Mie M, Ishii T, Ishida H, Saito JI, Nakai R Am J Cancer Res. 2021 Jan 1;11(1):264-276. eCollection 2021. PMID:33520373^[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
↑ Kinosada H, Okada-Iwasaki R, Kunieda K, Suzuki-Imaizumi M, Takahashi Y, Miyagi H, Suzuki M, Motosawa K, Watanabe M, Mie M, Ishii T, Ishida H, Saito JI, Nakai R. The dual pocket binding novel tankyrase inhibitor K-476 enhances the efficacy of immune checkpoint inhibitor by attracting CD8(+) T cells to tumors. Am J Cancer Res. 2021 Jan 1;11(1):264-276. eCollection 2021 PMID:33520373

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/7ce4"

Categories: Homo sapiens | Large Structures | Saito J | Suzuki M | Takahashi Y

@@ Line 1: / Line 1: @@
-====
+==Tankyrase2 catalytic domain in complex with K-476==
-<StructureSection load='7ce4' size='340' side='right'caption='[[7ce4]]' scene=''>
+<StructureSection load='7ce4' size='340' side='right'caption='[[7ce4]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7ce4]] is a 2 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=7CE4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CE4 FirstGlance]. <br>
-</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=7ce4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ce4 OCA], [https://pdbe.org/7ce4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ce4 RCSB], [https://www.ebi.ac.uk/pdbsum/7ce4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ce4 ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KK6:5-[3-[[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl]-2-oxidanylidene-4H-quinazolin-1-yl]-2-fluoranyl-benzenecarbonitrile'>KK6</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7ce4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ce4 OCA], [https://pdbe.org/7ce4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ce4 RCSB], [https://www.ebi.ac.uk/pdbsum/7ce4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ce4 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 Wnt/beta-catenin pathway, which is associated with disease progression, is activated in many cancers. Tankyrase (TNKS) has received attention as a target molecule for Wnt/beta-catenin pathway inhibition. We identified K-476, a novel TNKS inhibitor, a dual pocket binder that binds to both the nicotinamide and ADP-ribose pockets. In a human colon cancer cell line, K-476 specifically and potently inhibited TNKS and led to stabilization of the Axin protein, resulting in Wnt/beta-catenin pathway suppression. Aberrant Wnt/beta-catenin pathway activation was recently reported as a possible mechanism of ineffectiveness in immune checkpoint inhibitor (ICI) treatment. Because the Wnt/beta-catenin pathway activation causes dendritic cell inactivation and suppresses chemokine production, resulting in a paucity of CD8(+) T cells in tumor tissue, which is an important effector of ICIs. Thus, TNKS inhibitors may enhance the efficacy of ICIs. To examine whether K-476 enhances the antitumor effect of anti-PD-L1 antibodies, K-476 was administered orally with an anti-PD-L1 antibody to melanoma-bearing C57BL/6J mice. Although K-476 was ineffective as a monotherapy, it significantly enhanced the antitumor effect in combination with anti-PD-L1 antibody. In mice, intra-tumor infiltration of CD8(+) T cells was increased by combination treatment. K-476 upregulated the chemokine expression (e.g., Ccl3 and Ccl4), which attracted CD8(+) T cells. This was considered to contribute to the increased CD8(+) T cells in the tumor microenvironment. Furthermore, while the potential gastrointestinal toxicity of TNKS inhibitors has been reported, it was not observed at effective doses. Thus, K-476 could be an attractive therapeutic option to enhance the efficacy of ICIs.
+The dual pocket binding novel tankyrase inhibitor K-476 enhances the efficacy of immune checkpoint inhibitor by attracting CD8(+) T cells to tumors.,Kinosada H, Okada-Iwasaki R, Kunieda K, Suzuki-Imaizumi M, Takahashi Y, Miyagi H, Suzuki M, Motosawa K, Watanabe M, Mie M, Ishii T, Ishida H, Saito JI, Nakai R Am J Cancer Res. 2021 Jan 1;11(1):264-276. eCollection 2021. PMID:33520373<ref>PMID:33520373</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7ce4" 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: Z-disk]]
+[[Category: Saito J]]
+[[Category: Suzuki M]]
+[[Category: Takahashi Y]]

7ce4

From Proteopedia

Current revision

Tankyrase2 catalytic domain in complex with K-476

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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