6tx3
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==HPF1 bound to catalytic fragment of PARP2== | |
| + | <StructureSection load='6tx3' size='340' side='right'caption='[[6tx3]], [[Resolution|resolution]] 2.96Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6tx3]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TX3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6TX3 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=UHB:2-[4-[(2S,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-BIS(OXIDANYL)OXOLAN-2-YL]CARBONYLPIPERAZIN-1-YL]-N-(1-OXIDANYLIDENE-2,3-DIHYDROISOINDOL-4-YL)ETHANAMIDE'>UHB</scene></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=6tx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tx3 OCA], [http://pdbe.org/6tx3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tx3 RCSB], [http://www.ebi.ac.uk/pdbsum/6tx3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tx3 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/PARP2_HUMAN PARP2_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. [[http://www.uniprot.org/uniprot/HPF1_HUMAN HPF1_HUMAN]] Acts as a cofactor for serine ADP-ribosylation by conferring serine specificity on PARP1 and PARP2: interacts with PARP1 and PARP2 and is able to change amino acid specificity toward serine (PubMed:28190768, PubMed:29480802). Promotes histone serine ADP-ribosylation in response to DNA damage, limiting DNA damage-induced PARP1 hyper-automodification, and ensuring genome stability (PubMed:27067600, PubMed:28190768). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802). HPF1 also promotes tyrosine ADP-ribosylation, probably by conferring tyrosine specificity on PARP1 (PubMed:30257210).<ref>PMID:27067600</ref> <ref>PMID:28190768</ref> <ref>PMID:29480802</ref> <ref>PMID:30257210</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The anti-cancer drug target poly(ADP-ribose) polymerase 1 (PARP1) and its close homologue, PARP2, are early responders to DNA damage in human cells(1,2). Upon binding to genomic lesions, these enzymes utilise NAD(+) to modify a plethora of proteins with mono- and poly(ADP-ribose) signals that are important for subsequent chromatin decompaction and repair factor recruitment(3,4). These post-translational modification events are predominantly serine-linked and require HPF1, an accessory factor that is specific for the DNA damage response and switches the amino-acid specificity of PARP1/2 from aspartate/glutamate to serine residues(5-10). Here, we report a co-structure of HPF1 bound to the catalytic domain of PARP2 that, in combination with NMR and biochemical data, reveals a composite active site formed by residues from both PARP1/2 and HPF1. We further show that the assembly of this new catalytic centre is essential for DNA damage-induced protein ADP-ribosylation in human cells. In response to DNA damage and NAD(+) binding site occupancy, the HPF1-PARP1/2 interaction is enhanced via allosteric networks operating within PARP1/2, providing an additional level of regulation in DNA repair induction. As HPF1 forms a joint active site with PARP1/2, our data implicate HPF1 as an important determinant of the response to clinical PARP inhibitors. | ||
| - | + | HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation.,Suskiewicz MJ, Zobel F, Ogden TEH, Fontana P, Ariza A, Yang JC, Zhu K, Bracken L, Hawthorne WJ, Ahel D, Neuhaus D, Ahel I Nature. 2020 Feb 6. pii: 10.1038/s41586-020-2013-6. doi:, 10.1038/s41586-020-2013-6. PMID:32028527<ref>PMID:32028527</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6tx3" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Ahel, I]] | ||
| + | [[Category: Suskiewicz, M J]] | ||
| + | [[Category: Adp-ribosylation]] | ||
| + | [[Category: Artd2]] | ||
| + | [[Category: C4orf27]] | ||
| + | [[Category: Hpf1]] | ||
| + | [[Category: Parp2]] | ||
| + | [[Category: Serine adp-ribosylation]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 06:40, 19 February 2020
HPF1 bound to catalytic fragment of PARP2
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