|
|
| Line 3: |
Line 3: |
| | <StructureSection load='4b1g' size='340' side='right'caption='[[4b1g]], [[Resolution|resolution]] 1.83Å' scene=''> | | <StructureSection load='4b1g' size='340' side='right'caption='[[4b1g]], [[Resolution|resolution]] 1.83Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4b1g]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B1G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B1G FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4b1g]] 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=4B1G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B1G FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTV:(2S,3S)-1,4-DIMERCAPTOBUTANE-2,3-DIOL'>DTV</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]] 1.83Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTV:(2S,3S)-1,4-DIMERCAPTOBUTANE-2,3-DIOL'>DTV</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</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"><div style='overflow: auto; max-height: 3em;'>[[4a0d|4a0d]], [[4b1h|4b1h]], [[4b1i|4b1i]], [[4b1j|4b1j]]</div></td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Poly(ADP-ribose)_glycohydrolase Poly(ADP-ribose) glycohydrolase], with EC number [https://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=4b1g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b1g OCA], [https://pdbe.org/4b1g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b1g RCSB], [https://www.ebi.ac.uk/pdbsum/4b1g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b1g 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=4b1g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b1g OCA], [https://pdbe.org/4b1g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b1g RCSB], [https://www.ebi.ac.uk/pdbsum/4b1g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b1g ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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>
| + | [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 == |
| Line 28: |
Line 26: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Brassington, C]] | + | [[Category: Brassington C]] |
| - | [[Category: Ellston, J]] | + | [[Category: Ellston J]] |
| - | [[Category: Hassall, G]] | + | [[Category: Hassall G]] |
| - | [[Category: Holdgate, G]] | + | [[Category: Holdgate G]] |
| - | [[Category: McAlister, M]] | + | [[Category: McAlister M]] |
| - | [[Category: Overman, R]] | + | [[Category: Overman R]] |
| - | [[Category: Smith, G]] | + | [[Category: Smith G]] |
| - | [[Category: Tucker, J A]] | + | [[Category: Tucker JA]] |
| - | [[Category: Watson, M]] | + | [[Category: Watson M]] |
| - | [[Category: Hydrolase]]
| + | |
| 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
Poly(ADP-ribose) glycohydrolase (PARG) is the only enzyme known to catalyse hydrolysis of the O-glycosidic linkages of ADP-ribose polymers, thereby reversing the effects of poly(ADP-ribose) polymerases. PARG deficiency leads to cell death whilst PARG depletion causes sensitisation to certain DNA damaging agents, implicating PARG as a potential therapeutic target in several disease areas. Efforts to develop small molecule inhibitors of PARG activity have until recently been hampered by a lack of structural information on PARG. We have used a combination of bio-informatic and experimental approaches to engineer a crystallisable, catalytically active fragment of human PARG (hPARG). Here, we present high-resolution structures of the catalytic domain of hPARG in unliganded form and in complex with three inhibitors: ADP-ribose (ADPR), adenosine 5'-diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD) and 8-n-octyl-amino-ADP-HPD. Our structures confirm conservation of overall fold amongst mammalian PARG glycohydrolase domains, whilst revealing additional flexible regions in the catalytic site. These new structures rationalise a body of published mutational data and the reported structure-activity relationship for ADP-HPD based PARG inhibitors. In addition, we have developed and used biochemical, isothermal titration calorimetry and surface plasmon resonance assays to characterise the binding of inhibitors to our PARG protein, thus providing a starting point for the design of new inhibitors.
Structures of the Human Poly (ADP-Ribose) Glycohydrolase Catalytic Domain Confirm Catalytic Mechanism and Explain Inhibition by ADP-HPD Derivatives.,Tucker JA, Bennett N, Brassington C, Durant ST, Hassall G, Holdgate G, McAlister M, Nissink JW, Truman C, Watson M PLoS One. 2012;7(12):e50889. doi: 10.1371/journal.pone.0050889. Epub 2012 Dec 10. PMID:23251397[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
- ↑ Tucker JA, Bennett N, Brassington C, Durant ST, Hassall G, Holdgate G, McAlister M, Nissink JW, Truman C, Watson M. Structures of the Human Poly (ADP-Ribose) Glycohydrolase Catalytic Domain Confirm Catalytic Mechanism and Explain Inhibition by ADP-HPD Derivatives. PLoS One. 2012;7(12):e50889. doi: 10.1371/journal.pone.0050889. Epub 2012 Dec 10. PMID:23251397 doi:http://dx.doi.org/10.1371/journal.pone.0050889
|
