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| | ==POLYADPRIBOSYL GLYCOSIDASE IN COMPLEX WITH PDD00017262== | | ==POLYADPRIBOSYL GLYCOSIDASE IN COMPLEX WITH PDD00017262== |
| - | <StructureSection load='5lhb' size='340' side='right' caption='[[5lhb]], [[Resolution|resolution]] 2.23Å' scene=''> | + | <StructureSection load='5lhb' size='340' side='right'caption='[[5lhb]], [[Resolution|resolution]] 2.23Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5lhb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LHB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LHB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5lhb]] is a 1 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=5LHB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LHB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6WJ:1-(CYCLOPROPYLMETHYL)-6-[[(1-METHYLCYCLOPROPYL)AMINO]-BIS(OXIDANYL)-$L^{4}-SULFANYL]-3-[(2-METHYL-1,3-THIAZOL-5-YL)METHYL]QUINAZOLINE-2,4-DIONE'>6WJ</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.23Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=6WK:(2~{R})-2-AZANYL-3-[[(2~{S},3~{S})-2,3-BIS(OXIDANYL)-4-SULFANYL-BUTYL]DISULFANYL]PROPANOIC+ACID'>6WK</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6WJ:1-(CYCLOPROPYLMETHYL)-6-[[(1-METHYLCYCLOPROPYL)AMINO]-BIS(OXIDANYL)-$L^{4}-SULFANYL]-3-[(2-METHYL-1,3-THIAZOL-5-YL)METHYL]QUINAZOLINE-2,4-DIONE'>6WJ</scene>, <scene name='pdbligand=6WK:(2~{R})-2-AZANYL-3-[[(2~{S},3~{S})-2,3-BIS(OXIDANYL)-4-SULFANYL-BUTYL]DISULFANYL]PROPANOIC+ACID'>6WK</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Poly(ADP-ribose)_glycohydrolase Poly(ADP-ribose) glycohydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.143 3.2.1.143] </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=5lhb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lhb OCA], [https://pdbe.org/5lhb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lhb RCSB], [https://www.ebi.ac.uk/pdbsum/5lhb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lhb 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=5lhb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lhb OCA], [http://pdbe.org/5lhb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lhb RCSB], [http://www.ebi.ac.uk/pdbsum/5lhb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lhb ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PARG_HUMAN PARG_HUMAN]] Poly(ADP-ribose) synthesized after DNA damage is only present transiently and is rapidly degraded by poly(ADP-ribose) glycohydrolase. PARG acts both as an endo- and exoglycosidase, releasing PAR of different length as well as ADP-ribose monomers. Required for retinoid acid-dependent gene transactivation, probably by dePARsylating histone demethylase KDM4D, allowing chromatin derepression at RAR-dependent gene promoters.<ref>PMID:23102699</ref> | + | [https://www.uniprot.org/uniprot/PARG_HUMAN PARG_HUMAN] Poly(ADP-ribose) synthesized after DNA damage is only present transiently and is rapidly degraded by poly(ADP-ribose) glycohydrolase. PARG acts both as an endo- and exoglycosidase, releasing PAR of different length as well as ADP-ribose monomers. Required for retinoid acid-dependent gene transactivation, probably by dePARsylating histone demethylase KDM4D, allowing chromatin derepression at RAR-dependent gene promoters.<ref>PMID:23102699</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5lhb" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5lhb" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Poly(ADP-ribose) glycohydrolase 3D structures|Poly(ADP-ribose) glycohydrolase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Barkauskaite, E]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Tucker, J]] | + | [[Category: Large Structures]] |
| - | [[Category: Competitive inhibitor]] | + | [[Category: Barkauskaite E]] |
| - | [[Category: Hydrolase]] | + | [[Category: Tucker J]] |
| Structural highlights
Function
PARG_HUMAN Poly(ADP-ribose) synthesized after DNA damage is only present transiently and is rapidly degraded by poly(ADP-ribose) glycohydrolase. PARG acts both as an endo- and exoglycosidase, releasing PAR of different length as well as ADP-ribose monomers. Required for retinoid acid-dependent gene transactivation, probably by dePARsylating histone demethylase KDM4D, allowing chromatin derepression at RAR-dependent gene promoters.[1]
Publication Abstract from PubMed
The enzyme poly(ADP-ribose) glycohydrolase (PARG) performs a critical role in the repair of DNA single strand breaks (SSBs). However, a detailed understanding of its mechanism of action has been hampered by a lack of credible, cell-active chemical probes. Herein, we demonstrate inhibition of PARG with a small molecule, leading to poly(ADP-ribose) (PAR) chain persistence in intact cells. Moreover, we describe two advanced, and chemically distinct, cell-active tool compounds with convincing on-target pharmacology and selectivity. Using one of these tool compounds, we demonstrate pharmacology consistent with PARG inhibition. Further, while the roles of PARG and poly(ADP-ribose) polymerase (PARP) are closely intertwined, we demonstrate that the pharmacology of a PARG inhibitor differs from that observed with the more thoroughly studied PARP inhibitor olaparib. We believe that these tools will facilitate a wider understanding of this important component of DNA repair and may enable the development of novel therapeutic agents exploiting the critical dependence of tumors on the DNA damage response (DDR).
First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib.,James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ ACS Chem Biol. 2016 Oct 12. PMID:27689388[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Le May N, Iltis I, Ame JC, Zhovmer A, Biard D, Egly JM, Schreiber V, Coin F. Poly (ADP-ribose) glycohydrolase regulates retinoic acid receptor-mediated gene expression. Mol Cell. 2012 Dec 14;48(5):785-98. doi: 10.1016/j.molcel.2012.09.021. Epub 2012 , Oct 25. PMID:23102699 doi:http://dx.doi.org/10.1016/j.molcel.2012.09.021
- ↑ James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12. PMID:27689388 doi:http://dx.doi.org/10.1021/acschembio.6b00609
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