7pwq: Difference between revisions
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==PARP15 catalytic domain in complex with OUL240== | ==PARP15 catalytic domain in complex with OUL240== | ||
<StructureSection load='7pwq' size='340' side='right'caption='[[7pwq]]' scene=''> | <StructureSection load='7pwq' size='340' side='right'caption='[[7pwq]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PWQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PWQ FirstGlance]. <br> | <table><tr><td colspan='2'>[[7pwq]] 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=7PWQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PWQ 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=7pwq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pwq OCA], [https://pdbe.org/7pwq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pwq RCSB], [https://www.ebi.ac.uk/pdbsum/7pwq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pwq 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]] 1.7Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8A8:6-(cyclohexylmethoxy)phthalazine-1,4-dione'>8A8</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</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=7pwq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pwq OCA], [https://pdbe.org/7pwq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pwq RCSB], [https://www.ebi.ac.uk/pdbsum/7pwq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pwq ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/PAR15_HUMAN PAR15_HUMAN] Transcriptional repressor. Has ADP-ribosyltransferase activity. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
While human poly-ADP-ribose chain generating poly-ARTs, PARP1 and 2 and TNKS1 and 2, have been widely characterized, less is known on the pathophysiological roles of the mono-ADP-ribosylating mono-ARTs, partly due to the lack of selective inhibitors. In this context, we have focused on the development of inhibitors for the mono-ART PARP10, whose overexpression is known to induce cell death. Starting from OUL35 (1) and its 4-(benzyloxy)benzamidic derivative (2) we herein report the design and synthesis of new analogues from which the cyclobutyl derivative 3c rescued cells most efficiently from PARP10 induced apoptosis. Most importantly, we also identified 2,3-dihydrophthalazine-1,4-dione as a new suitable nicotinamide mimicking PARP10 inhibitor scaffold. When it was functionalized with cycloalkyl (8a-c), o-fluorophenyl (8h), and thiophene (8l) rings, IC50 values in the 130-160 nM range were obtained, making them the most potent PARP10 inhibitors reported to date. These compounds also inhibited PARP15 with low micromolar IC50s, but none of the other tested poly- and mono-ARTs, thus emerging as dual mono-ART inhibitors. Compounds 8a, 8h and 8l were also able to enter cells and rescue cells from apoptosis. Our work sheds more light on inhibitor development against mono-ARTs and identifies chemical probes to study the cellular roles of PARP10 and PARP15. | |||
Potent 2,3-dihydrophthalazine-1,4-dione derivatives as dual inhibitors for mono-ADP-ribosyltransferases PARP10 and PARP15.,Nizi MG, Maksimainen MM, Murthy S, Massari S, Alaviuhkola J, Lippok BE, Sowa ST, Galera-Prat A, Prunskaite-Hyyrylainen R, Luscher B, Korn P, Lehtio L, Tabarrini O Eur J Med Chem. 2022 Apr 19;237:114362. doi: 10.1016/j.ejmech.2022.114362. PMID:35500474<ref>PMID:35500474</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7pwq" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Lehtio L]] | [[Category: Lehtio L]] | ||
[[Category: Maksimainen MM]] | [[Category: Maksimainen MM]] | ||