6o9x

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<StructureSection load='6o9x' size='340' side='right'caption='[[6o9x]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
<StructureSection load='6o9x' size='340' side='right'caption='[[6o9x]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6o9x]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O9X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O9X FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6o9x]] 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=6O9X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O9X FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=M0S:1,3-dimethyl-8-{[2-(pyrrolidin-1-yl)ethyl]sulfanyl}-6-sulfanylidene-1,3,6,9-tetrahydro-2H-purin-2-one'>M0S</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
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<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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=M0S:1,3-dimethyl-8-{[2-(pyrrolidin-1-yl)ethyl]sulfanyl}-6-sulfanylidene-1,3,6,9-tetrahydro-2H-purin-2-one'>M0S</scene></td></tr>
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<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=6o9x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o9x OCA], [http://pdbe.org/6o9x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o9x RCSB], [http://www.ebi.ac.uk/pdbsum/6o9x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o9x ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6o9x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o9x OCA], [https://pdbe.org/6o9x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o9x RCSB], [https://www.ebi.ac.uk/pdbsum/6o9x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o9x ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Poly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We employed chemical library screening to identify and optimize methylxanthine derivatives as selective bioavailable PARG inhibitors. Multiple crystal structures reveal how substituent positions on the methylxanthine core dictate binding modes and inducible-complementarity with a PARG-specific tyrosine clasp and arginine switch, supporting inhibitor specificity and a competitive inhibition mechanism. Cell-based assays show selective PARG inhibition and PARP1 hyperPARylation. Moreover, our PARG inhibitor sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression and impedes cancer cell survival. In PARP inhibitor-resistant A172 glioblastoma cells, our PARG inhibitor shows comparable killing to Nedaplatin, providing further proof-of-concept that selectively inhibiting PARG can impair cancer cell survival.
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Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death.,Houl JH, Ye Z, Brosey CA, Balapiti-Modarage LPF, Namjoshi S, Bacolla A, Laverty D, Walker BL, Pourfarjam Y, Warden LS, Babu Chinnam N, Moiani D, Stegeman RA, Chen MK, Hung MC, Nagel ZD, Ellenberger T, Kim IK, Jones DE, Ahmed Z, Tainer JA Nat Commun. 2019 Dec 11;10(1):5654. doi: 10.1038/s41467-019-13508-4. PMID:31827085<ref>PMID:31827085</ref>
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==See Also==
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*[[Poly(ADP-ribose) glycohydrolase 3D structures|Poly(ADP-ribose) glycohydrolase 3D structures]]
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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 6o9x" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Ellenberger, T]]
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[[Category: Ellenberger T]]
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[[Category: Jones, D E]]
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[[Category: Jones DE]]
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[[Category: Kim, I K]]
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[[Category: Kim IK]]
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[[Category: Stegeman, R A]]
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[[Category: Stegeman RA]]
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[[Category: Tainer, J A]]
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[[Category: Tainer JA]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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Current revision

Structure of human PARG complexed with JA2-4

PDB ID 6o9x

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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