|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Human tankyrase 2 - catalytic PARP domain in complex with 2-(2-pyridyl)-7,8-dihydro-5h-thiino[4,3-d]pyrimidin-4-ol== | | ==Human tankyrase 2 - catalytic PARP domain in complex with 2-(2-pyridyl)-7,8-dihydro-5h-thiino[4,3-d]pyrimidin-4-ol== |
| - | <StructureSection load='3mhk' size='340' side='right' caption='[[3mhk]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='3mhk' size='340' side='right'caption='[[3mhk]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3mhk]] 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=3MHK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MHK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3mhk]] is a 1 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=3MHK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MHK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=P4L:2-PYRIDIN-2-YL-7,8-DIHYDRO-5H-THIOPYRANO[4,3-D]PYRIMIDIN-4-OL'>P4L</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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]] 2.3Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3kr7|3kr7]], [[3kr8|3kr8]], [[3mhj|3mhj]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=P4L:2-PYRIDIN-2-YL-7,8-DIHYDRO-5H-THIOPYRANO[4,3-D]PYRIMIDIN-4-OL'>P4L</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PARP5B, TANK2, TNKL, TNKS2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3mhk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mhk OCA], [https://pdbe.org/3mhk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mhk RCSB], [https://www.ebi.ac.uk/pdbsum/3mhk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mhk ProSAT]</span></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=3mhk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mhk OCA], [http://pdbe.org/3mhk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3mhk RCSB], [http://www.ebi.ac.uk/pdbsum/3mhk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3mhk ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Line 33: |
Line 31: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Poly (ADP-ribose) polymerase|Poly (ADP-ribose) polymerase]] | + | *[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Large Structures]] |
| - | [[Category: Berg, S Van Den]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Berglund, H]] | + | [[Category: Berglund H]] |
| - | [[Category: Bountra, C]] | + | [[Category: Bountra C]] |
| - | [[Category: Collins, R]] | + | [[Category: Collins R]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Edwards AM]] |
| - | [[Category: Flodin, S]] | + | [[Category: Flodin S]] |
| - | [[Category: Flores, A]] | + | [[Category: Flores A]] |
| - | [[Category: Graslund, S]] | + | [[Category: Graslund S]] |
| - | [[Category: Hammarstrom, M]] | + | [[Category: Hammarstrom M]] |
| - | [[Category: Johansson, I]] | + | [[Category: Johansson I]] |
| - | [[Category: Karlberg, T]] | + | [[Category: Karlberg T]] |
| - | [[Category: Kotenyova, T]] | + | [[Category: Kotenyova T]] |
| - | [[Category: Markova, N]] | + | [[Category: Markova N]] |
| - | [[Category: Moche, M]] | + | [[Category: Moche M]] |
| - | [[Category: Nordlund, P]] | + | [[Category: Nordlund P]] |
| - | [[Category: Nyman, T]] | + | [[Category: Nyman T]] |
| - | [[Category: Persson, C]] | + | [[Category: Persson C]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Schuler H]] |
| - | [[Category: Schuler, H]] | + | [[Category: Schutz P]] |
| - | [[Category: Schutz, P]] | + | [[Category: Siponen MI]] |
| - | [[Category: Siponen, M I]] | + | [[Category: Svensson L]] |
| - | [[Category: Svensson, L]] | + | [[Category: Thorsell AG]] |
| - | [[Category: Thorsell, A G]] | + | [[Category: Tresaugues L]] |
| - | [[Category: Tresaugues, L]] | + | [[Category: Van Den Berg S]] |
| - | [[Category: Weigelt, J]] | + | [[Category: Weigelt J]] |
| - | [[Category: Welin, M]] | + | [[Category: Welin M]] |
| - | [[Category: Wisniewska, M]] | + | [[Category: Wisniewska M]] |
| - | [[Category: Adp-ribosylation]] | + | |
| - | [[Category: Ank repeat]]
| + | |
| - | [[Category: Catalytic fragment]]
| + | |
| - | [[Category: Chromosomal protein]]
| + | |
| - | [[Category: Glycosyltransferase]]
| + | |
| - | [[Category: Golgi apparatus]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Mrna transport]]
| + | |
| - | [[Category: Nad]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Parp]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Protein transport]]
| + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Telomere]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Translocation]]
| + | |
| - | [[Category: Transport]]
| + | |
| - | [[Category: Wnt-signalling]]
| + | |
| Structural highlights
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Inhibitors of poly-ADP-ribose polymerase (PARP) family proteins are currently in clinical trials as cancer therapeutics, yet the specificity of many of these compounds is unknown. Here we evaluated a series of 185 small-molecule inhibitors, including research reagents and compounds being tested clinically, for the ability to bind to the catalytic domains of 13 of the 17 human PARP family members including the tankyrases, TNKS1 and TNKS2. Many of the best-known inhibitors, including TIQ-A, 6(5H)-phenanthridinone, olaparib, ABT-888 and rucaparib, bound to several PARP family members, suggesting that these molecules lack specificity and have promiscuous inhibitory activity. We also determined X-ray crystal structures for five TNKS2 ligand complexes and four PARP14 ligand complexes. In addition to showing that the majority of PARP inhibitors bind multiple targets, these results provide insight into the design of new inhibitors.
Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors.,Wahlberg E, Karlberg T, Kouznetsova E, Markova N, Macchiarulo A, Thorsell AG, Pol E, Frostell A, Ekblad T, Oncu D, Kull B, Robertson GM, Pellicciari R, Schuler H, Weigelt J Nat Biotechnol. 2012 Feb 19. doi: 10.1038/nbt.2121. PMID:22343925[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Wahlberg E, Karlberg T, Kouznetsova E, Markova N, Macchiarulo A, Thorsell AG, Pol E, Frostell A, Ekblad T, Oncu D, Kull B, Robertson GM, Pellicciari R, Schuler H, Weigelt J. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat Biotechnol. 2012 Feb 19. doi: 10.1038/nbt.2121. PMID:22343925 doi:10.1038/nbt.2121
|
