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| <StructureSection load='5a7r' size='340' side='right'caption='[[5a7r]], [[Resolution|resolution]] 1.95Å' scene=''> | | <StructureSection load='5a7r' size='340' side='right'caption='[[5a7r]], [[Resolution|resolution]] 1.95Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
- | <table><tr><td colspan='2'>[[5a7r]] 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=5A7R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5A7R FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5a7r]] 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=5A7R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5A7R FirstGlance]. <br> |
- | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AR6:[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL+[HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL]+HYDROGEN+PHOSPHATE'>AR6</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PPI:PROPANOIC+ACID'>PPI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AR6:[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL+[HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL]+HYDROGEN+PHOSPHATE'>AR6</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PPI:PROPANOIC+ACID'>PPI</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=5a7r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a7r OCA], [https://pdbe.org/5a7r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5a7r RCSB], [https://www.ebi.ac.uk/pdbsum/5a7r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5a7r 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=5a7r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a7r OCA], [http://pdbe.org/5a7r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5a7r RCSB], [http://www.ebi.ac.uk/pdbsum/5a7r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5a7r 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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| | | |
| ==See Also== | | ==See Also== |
- | *[[Poly (ADP-ribose) glycohydrolase|Poly (ADP-ribose) glycohydrolase]] | + | *[[Poly(ADP-ribose) glycohydrolase 3D structures|Poly(ADP-ribose) glycohydrolase 3D structures]] |
| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
- | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
- | [[Category: Ahel, I]] | + | [[Category: Ahel I]] |
- | [[Category: Ariza, A]] | + | [[Category: Ariza A]] |
- | [[Category: Barkauskaite, E]] | + | [[Category: Barkauskaite E]] |
- | [[Category: Brichacek, M]] | + | [[Category: Brichacek M]] |
- | [[Category: Hergenrother, P J]] | + | [[Category: Hergenrother PJ]] |
- | [[Category: Lambrecht, M J]] | + | [[Category: Lambrecht MJ]] |
- | [[Category: Adp-ribose]]
| + | |
- | [[Category: Hydrolase]]
| + | |
- | [[Category: Parg]]
| + | |
| 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-ribosyl)ation is a common post-translational modification that mediates a wide variety of cellular processes including DNA damage repair, chromatin regulation, transcription, and apoptosis. The difficulty associated with accessing poly(ADP-ribose) (PAR) in a homogeneous form has been an impediment to understanding the interactions of PAR with poly(ADP-ribose) glycohydrolase (PARG) and other binding proteins. Here we describe the chemical synthesis of the ADP-ribose dimer, and we use this compound to obtain the first human PARG substrate-enzyme cocrystal structure. Chemical synthesis of PAR is an attractive alternative to traditional enzymatic synthesis and fractionation, allowing access to products such as dimeric ADP-ribose, which has been detected but never isolated from natural sources. Additionally, we describe the synthesis of an alkynylated dimer and demonstrate that this compound can be used to synthesize PAR probes including biotin and fluorophore-labeled compounds. The fluorescently labeled ADP-ribose dimer was then utilized in a general fluorescence polarization-based PAR-protein binding assay. Finally, we use intermediates of our synthesis to access various PAR fragments, and evaluation of these compounds as substrates for PARG reveals the minimal features for substrate recognition and enzymatic cleavage. Homogeneous PAR oligomers and unnatural variants produced from chemical synthesis will allow for further detailed structural and biochemical studies on the interaction of PAR with its many protein binding partners.
Synthesis of dimeric ADP-ribose and its structure with human poly(ADP-ribose) glycohydrolase.,Lambrecht MJ, Brichacek M, Barkauskaite E, Ariza A, Ahel I, Hergenrother PJ J Am Chem Soc. 2015 Mar 18;137(10):3558-64. doi: 10.1021/ja512528p. Epub 2015 Mar, 4. PMID:25706250[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
- ↑ Lambrecht MJ, Brichacek M, Barkauskaite E, Ariza A, Ahel I, Hergenrother PJ. Synthesis of dimeric ADP-ribose and its structure with human poly(ADP-ribose) glycohydrolase. J Am Chem Soc. 2015 Mar 18;137(10):3558-64. doi: 10.1021/ja512528p. Epub 2015 Mar, 4. PMID:25706250 doi:http://dx.doi.org/10.1021/ja512528p
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