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6xvw
From Proteopedia
(Difference between revisions)
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==Catalytic domain of human PARP-1 in complex with the inhibitor MC2050== | ==Catalytic domain of human PARP-1 in complex with the inhibitor MC2050== | ||
| - | <StructureSection load='6xvw' size='340' side='right'caption='[[6xvw]]' scene=''> | + | <StructureSection load='6xvw' size='340' side='right'caption='[[6xvw]], [[Resolution|resolution]] 2.00Å' 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=6XVW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XVW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6xvw]] 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=6XVW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XVW 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=6xvw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xvw OCA], [https://pdbe.org/6xvw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xvw RCSB], [https://www.ebi.ac.uk/pdbsum/6xvw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xvw 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]] 2Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=O3H:2-[2-(4-pyridin-2-ylpiperazin-1-yl)ethylsulfanyl]-3~{H}-quinazolin-4-one'>O3H</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=6xvw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xvw OCA], [https://pdbe.org/6xvw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xvw RCSB], [https://www.ebi.ac.uk/pdbsum/6xvw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xvw ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/PARP1_HUMAN PARP1_HUMAN] Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP-ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production.<ref>PMID:17177976</ref> <ref>PMID:18172500</ref> <ref>PMID:19344625</ref> <ref>PMID:19661379</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Tankyrases (TNKSs) have recently gained great consideration as potential targets in Wnt/beta-catenin pathway-dependent solid tumors. Previously, we reported the 2-mercaptoquinazolin-4-one MC2050 as a micromolar PARP1 inhibitor. Here we show how the resolution of the X-ray structure of PARP1 in complex with MC2050, combined with the computational investigation of the structural differences between TNKSs and PARP1/2 active sites, provided the rationale for a structure-based drug design campaign that with a limited synthetic effort led to the discovery of the bis-quinazolinone 5 as a picomolar and selective TNKS2 inhibitor, endowed with antiproliferative effects in a colorectal cancer cell line (DLD-1) where the Wnt pathway is constitutively activated. | ||
| + | |||
| + | From PARP1 to TNKS2 Inhibition: A Structure-Based Approach.,Tomassi S, Pfahler J, Mautone N, Rovere A, Esposito C, Passeri D, Pellicciari R, Novellino E, Pannek M, Steegborn C, Paiardini A, Mai A, Rotili D ACS Med Chem Lett. 2020 Feb 3;11(5):862-868. doi: 10.1021/acsmedchemlett.9b00654. , eCollection 2020 May 14. PMID:32435397<ref>PMID:32435397</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6xvw" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]] | *[[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: Pfahler | + | [[Category: Pfahler J]] |
| + | [[Category: Steegborn C]] | ||
Current revision
Catalytic domain of human PARP-1 in complex with the inhibitor MC2050
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