4l6s
From Proteopedia
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4l6s]] 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=4L6S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L6S FirstGlance]. <br> | <table><tr><td colspan='2'>[[4l6s]] 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=4L6S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L6S FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1WQ:(2S)-6-{[4-(4-CHLOROPHENYL)-3,6-DIHYDROPYRIDIN-1(2H)-YL]METHYL}-2-METHYL-2H-1,4-BENZOXAZIN-3(4H)-ONE'>1WQ</scene></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]] 2.2Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1WQ:(2S)-6-{[4-(4-CHLOROPHENYL)-3,6-DIHYDROPYRIDIN-1(2H)-YL]METHYL}-2-METHYL-2H-1,4-BENZOXAZIN-3(4H)-ONE'>1WQ</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=4l6s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l6s OCA], [https://pdbe.org/4l6s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l6s RCSB], [https://www.ebi.ac.uk/pdbsum/4l6s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l6s ProSAT]</span></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=4l6s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l6s OCA], [https://pdbe.org/4l6s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l6s RCSB], [https://www.ebi.ac.uk/pdbsum/4l6s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l6s ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == 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> | [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 == | ||
| - | Structure based drug design of a series of novel 1,4-benzoxazin-3-one derived PARP-1 inhibitors are described. The synthesis, enzymatic & cellular activities and pharmacodynamic effects are described. Optimized analogs demonstrated inhibition of poly-ADP-ribosylation in SW620 tumor bearing nude mice through 24h following a single dose. | ||
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| - | Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors.,Gangloff AR, Brown J, de Jong R, Dougan DR, Grimshaw CE, Hixon M, Jennings A, Kamran R, Kiryanov A, O'Connell S, Taylor E, Vu P Bioorg Med Chem Lett. 2013 Aug 15;23(16):4501-5. doi: 10.1016/j.bmcl.2013.06.055., Epub 2013 Jun 24. PMID:23850199<ref>PMID:23850199</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4l6s" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
Current revision
PARP complexed with benzo[1,4]oxazin-3-one inhibitor
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