6nrf: Difference between revisions
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<StructureSection load='6nrf' size='340' side='right'caption='[[6nrf]], [[Resolution|resolution]] 2.00Å' scene=''> | <StructureSection load='6nrf' size='340' side='right'caption='[[6nrf]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6nrf]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NRF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NRF FirstGlance]. <br> | <table><tr><td colspan='2'>[[6nrf]] is a 1 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=6NRF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NRF FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=KYV:2-({4-[4-(1H-benzimidazol-2-yl)piperazine-1-carbonyl]phenyl}methyl)-3-hydroxy-1-benzofuran-7-carboxamide'>KYV</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=KYV:2-({4-[4-(1H-benzimidazol-2-yl)piperazine-1-carbonyl]phenyl}methyl)-3-hydroxy-1-benzofuran-7-carboxamide'>KYV</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PARP1, ADPRT, PPOL ([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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6nrf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nrf OCA], [http://pdbe.org/6nrf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nrf RCSB], [http://www.ebi.ac.uk/pdbsum/6nrf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nrf ProSAT]</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=6nrf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nrf OCA], [http://pdbe.org/6nrf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nrf RCSB], [http://www.ebi.ac.uk/pdbsum/6nrf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nrf ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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</div> | </div> | ||
<div class="pdbe-citations 6nrf" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6nrf" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Langelier, M F]] | [[Category: Langelier, M F]] | ||
Revision as of 12:23, 8 January 2020
Crystal Structure of human PARP-1 ART domain bound to inhibitor UTT103Crystal Structure of human PARP-1 ART domain bound to inhibitor UTT103
Structural highlights
Function[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.[1] [2] [3] [4] Publication Abstract from PubMedPoly(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[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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