View source for 3mhk


==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]] 2.30&Aring;' scene=''>
== Structural highlights ==
<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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</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='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>
</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> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mh/3mhk_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3mhk ConSurf].
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== 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<ref>PMID:22343925</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3mhk" 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: Arrowsmith CH]]
[[Category: Berglund H]]
[[Category: Bountra C]]
[[Category: Collins R]]
[[Category: Edwards AM]]
[[Category: Flodin S]]
[[Category: Flores A]]
[[Category: Graslund S]]
[[Category: Hammarstrom M]]
[[Category: Johansson I]]
[[Category: Karlberg T]]
[[Category: Kotenyova T]]
[[Category: Markova N]]
[[Category: Moche M]]
[[Category: Nordlund P]]
[[Category: Nyman T]]
[[Category: Persson C]]
[[Category: Schuler H]]
[[Category: Schutz P]]
[[Category: Siponen MI]]
[[Category: Svensson L]]
[[Category: Thorsell AG]]
[[Category: Tresaugues L]]
[[Category: Van Den Berg S]]
[[Category: Weigelt J]]
[[Category: Welin M]]
[[Category: Wisniewska M]]