7cmw

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==Complex structure of PARP1 catalytic domain with pamiparib==
==Complex structure of PARP1 catalytic domain with pamiparib==
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<StructureSection load='7cmw' size='340' side='right'caption='[[7cmw]]' scene=''>
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<StructureSection load='7cmw' size='340' side='right'caption='[[7cmw]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CMW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7CMW FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7cmw]] is a 2 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=7CMW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7CMW FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7cmw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cmw OCA], [http://pdbe.org/7cmw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7cmw RCSB], [http://www.ebi.ac.uk/pdbsum/7cmw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7cmw ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DS9:(2R)-14-fluoro-2-methyl-6,9,10,19-tetrazapentacyclo[14.2.1.02,6.08,18.012,17]nonadeca-1(18),8,12(17),13,15-pentaen-11-one'>DS9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7cmw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cmw OCA], [http://pdbe.org/7cmw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7cmw RCSB], [http://www.ebi.ac.uk/pdbsum/7cmw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7cmw ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC50 of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC50 = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.
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Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development.,Wang H, Ren B, Liu Y, Jiang B, Guo Y, Wei M, Luo L, Kuang X, Qiu M, Lv L, Xu H, Qi R, Yan H, Xu D, Wang Z, Huo CX, Zhu Y, Zhao Y, Wu Y, Qin Z, Su D, Tang T, Wang F, Sun X, Feng Y, Peng H, Wang X, Gao Y, Liu Y, Gong W, Yu F, Liu X, Wang L, Zhou C J Med Chem. 2020 Dec 2. doi: 10.1021/acs.jmedchem.0c01346. PMID:33264017<ref>PMID:33264017</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7cmw" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Feng YC]]
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[[Category: Feng, Y C]]
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[[Category: Hong Y]]
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[[Category: Hong, Y]]
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[[Category: Liu Y]]
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[[Category: Liu, Y]]
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[[Category: Peng H]]
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[[Category: Peng, H]]
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[[Category: Antitumor protein]]
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[[Category: Bgb-290]]
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[[Category: Pamiparib]]
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[[Category: Parp1]]
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[[Category: Transferase]]

Revision as of 06:04, 20 January 2021

Complex structure of PARP1 catalytic domain with pamiparib

PDB ID 7cmw

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