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| | ==Crystal structure of human PARP14 bound to 2-{[(1-methylpiperidin-4-yl)methyl]amino}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one inhibitor== | | ==Crystal structure of human PARP14 bound to 2-{[(1-methylpiperidin-4-yl)methyl]amino}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one inhibitor== |
| - | <StructureSection load='5v7w' size='340' side='right' caption='[[5v7w]], [[Resolution|resolution]] 2.65Å' scene=''> | + | <StructureSection load='5v7w' size='340' side='right'caption='[[5v7w]], [[Resolution|resolution]] 2.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5v7w]] 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=5V7W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V7W FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5v7w]] 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=5V7W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V7W FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=91J:2-{[(1-METHYLPIPERIDIN-4-YL)METHYL]AMINO}-5,6,7,8-TETRAHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-4(3H)-ONE'>91J</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]] 2.65Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v7t|5v7t]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=91J:2-{[(1-METHYLPIPERIDIN-4-YL)METHYL]AMINO}-5,6,7,8-TETRAHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-4(3H)-ONE'>91J</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PARP14, BAL2, KIAA1268 ([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=5v7w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v7w OCA], [https://pdbe.org/5v7w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v7w RCSB], [https://www.ebi.ac.uk/pdbsum/5v7w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v7w 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=5v7w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v7w OCA], [http://pdbe.org/5v7w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v7w RCSB], [http://www.ebi.ac.uk/pdbsum/5v7w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v7w ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PAR14_HUMAN PAR14_HUMAN]] Enhances STAT6-dependent transcription (By similarity). Has ADP-ribosyltransferase activity. | + | [https://www.uniprot.org/uniprot/PAR14_HUMAN PAR14_HUMAN] Enhances STAT6-dependent transcription (By similarity). Has ADP-ribosyltransferase activity. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==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: Hirozane, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Saikatendu, k s]] | + | [[Category: Hirozane M]] |
| - | [[Category: Human parp14]] | + | [[Category: Saikatendu ks]] |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
PAR14_HUMAN Enhances STAT6-dependent transcription (By similarity). Has ADP-ribosyltransferase activity.
Publication Abstract from PubMed
Poly(ADP-ribose) polymerases (PARPs) use nicotinamide adenine dinucleotide (NAD+) as a co-substrate to transfer ADP-ribose when it releases nicotinamide as the metabolized product. Enzymes of the PARP family play key roles in detecting and repairing DNA, modifying chromatin, regulating transcription, controlling energy metabolism, and inducing cell death. PARP14, the original member of the PARP family, has been reported to be associated with the development of inflammatory diseases and various cancer types, making it a potential therapeutic target. In this study, we purified the macrodomain-containing PARP14 enzyme and established an assay for detecting the auto-ribosylation activity of PARP14 using RapidFire high-throughput mass spectrometry and immunoradiometric assay using [3H]NAD+. Subsequently, we performed high-throughput screening using the assays and identified small-molecule hit compounds, which showed NAD+-competitive and PARP14-selective inhibitory activities. Co-crystal structures of PARP14 with certain hit compounds revealed that the inhibitors bind to the NAD+-binding site. Finally, we confirmed that the hit compounds interacted with intracellular PARP14 by a cell-based protein stabilization assay. Thus, we successfully identified primary candidate compounds for further investigation.
Identification of PARP14 inhibitors using novel methods for detecting auto-ribosylation.,Yoneyama-Hirozane M, Matsumoto SI, Toyoda Y, Saikatendu KS, Zama Y, Yonemori K, Oonishi M, Ishii T, Kawamoto T Biochem Biophys Res Commun. 2017 May 6;486(3):626-631. doi:, 10.1016/j.bbrc.2017.03.052. Epub 2017 Mar 14. PMID:28315326[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yoneyama-Hirozane M, Matsumoto SI, Toyoda Y, Saikatendu KS, Zama Y, Yonemori K, Oonishi M, Ishii T, Kawamoto T. Identification of PARP14 inhibitors using novel methods for detecting auto-ribosylation. Biochem Biophys Res Commun. 2017 May 6;486(3):626-631. doi:, 10.1016/j.bbrc.2017.03.052. Epub 2017 Mar 14. PMID:28315326 doi:http://dx.doi.org/10.1016/j.bbrc.2017.03.052
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