View source for 6nrh


==Crystal Structure of human PARP-1 ART domain bound inhibitor UTT63==
<StructureSection load='6nrh' size='340' side='right'caption='[[6nrh]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6nrh]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NRH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NRH FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=KYP:3-hydroxy-2-({4-[4-(pyrimidin-2-yl)piperazine-1-carbonyl]phenyl}methyl)-1-benzofuran-7-carboxamide'>KYP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6nrf|6nrf]], [[6nrg|6nrg]]</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=6nrh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nrh OCA], [http://pdbe.org/6nrh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nrh RCSB], [http://www.ebi.ac.uk/pdbsum/6nrh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nrh ProSAT]</span></td></tr>
</table>
== Function ==
[[http://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 ==
Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC50 = 434 nM) led to a tetrazolyl analogue (51, IC50 = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC50 = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC50 values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC50 values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC50 = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.

Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.,Velagapudi UK, Langelier MF, Delgado-Martin C, Diolaiti ME, Bakker S, Ashworth A, Patel BA, Shao X, Pascal JM, Talele TT J Med Chem. 2019 Jun 13;62(11):5330-5357. doi: 10.1021/acs.jmedchem.8b01709. Epub, 2019 May 24. PMID:31042381<ref>PMID:31042381</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6nrh" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Langelier, M F]]
[[Category: Pascal, J M]]
[[Category: Artd1]]
[[Category: Parp inhibitor]]
[[Category: Parp-1]]
[[Category: Parp1]]
[[Category: Transferase]]
[[Category: Transferase-transferase inhibitor complex]]