View source for 4hhy


==Crystal structure of PARP catalytic domain in complex with novel inhibitors==
<StructureSection load='4hhy' size='340' side='right'caption='[[4hhy]], [[Resolution|resolution]] 2.36&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4hhy]] is a 4 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=4HHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HHY 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]] 2.3637&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=15R:(9AR)-1-[(1-{2-FLUORO-5-[(4-OXO-3,4-DIHYDROPHTHALAZIN-1-YL)METHYL]BENZOYL}PIPERIDIN-4-YL)CARBONYL]-1,2,3,8,9,9A-HEXAHYDRO-7H-BENZO[DE][1,7]NAPHTHYRIDIN-7-ONE'>15R</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4hhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hhy OCA], [https://pdbe.org/4hhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hhy RCSB], [https://www.ebi.ac.uk/pdbsum/4hhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hhy ProSAT]</span></td></tr>
</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 ==
A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 &lt; 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.

Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors.,Ye N, Chen CH, Chen T, Song Z, He JX, Huan XJ, Song SS, Liu Q, Chen Y, Ding J, Xu Y, Miao ZH, Zhang A J Med Chem. 2013 Mar 21. PMID:23473053<ref>PMID:23473053</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4hhy" style="background-color:#fffaf0;"></div>

==See Also==
*[[Poly (ADP-ribose) polymerase|Poly (ADP-ribose) polymerase]]
*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen TT]]
[[Category: Liu QF]]
[[Category: Xu YC]]