9rfe
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | The entry | + | ==Human ADP-ribosylhydrolase 3 (ARH3) in complex with an inhibitor== |
| + | <StructureSection load='9rfe' size='340' side='right'caption='[[9rfe]], [[Resolution|resolution]] 1.85Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9rfe]] is a 2 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=9RFE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9RFE FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JFJ:2-[(2~{E})-2-[1-(4-aminophenyl)ethylidene]hydrazinyl]-6-methyl-1~{H}-pyrimidin-4-one'>A1JFJ</scene>, <scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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=9rfe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9rfe OCA], [https://pdbe.org/9rfe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9rfe RCSB], [https://www.ebi.ac.uk/pdbsum/9rfe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9rfe ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/ADPRS_HUMAN ADPRS_HUMAN] The disease is caused by variants affecting the gene represented in this entry. | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/ADPRS_HUMAN ADPRS_HUMAN] ADP-ribose glycohydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1'' position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose (PubMed:21498885, PubMed:30045870, PubMed:29907568, PubMed:30401461, PubMed:33186521). Specifically acts as a serine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response (PubMed:28650317, PubMed:29234005, PubMed:30045870, PubMed:33186521). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802, PubMed:33186521). Does not hydrolyze ADP-ribosyl-arginine, -cysteine, -diphthamide, or -asparagine bonds (PubMed:16278211). Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos (PubMed:16278211). Also hydrolyzes free poly(ADP-ribose) in mitochondria (PubMed:22433848). Specifically digests O-acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins (PubMed:17075046, PubMed:21498885). Specifically degrades 1''-O-acetyl-ADP-D-ribose isomer, rather than 2''-O-acetyl-ADP-D-ribose or 3''-O-acetyl-ADP-D-ribose isomers (PubMed:21498885).<ref>PMID:16278211</ref> <ref>PMID:17075046</ref> <ref>PMID:21498885</ref> <ref>PMID:22433848</ref> <ref>PMID:28650317</ref> <ref>PMID:29234005</ref> <ref>PMID:29480802</ref> <ref>PMID:29907568</ref> <ref>PMID:30045870</ref> <ref>PMID:30401461</ref> <ref>PMID:33186521</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Poly-ADP-ribosylation at sites of DNA damage, catalyzed by PARP enzymes, activates the DNA damage response, chromatin remodeling, and DNA repair. The modification is reversed by two enzymes in humans: PARG, which efficiently hydrolyzes the poly-ADP-ribose chains, and ARH3, which is the key enzyme for removing the last proximal mono-ADP-ribose from serine residues. While inhibitor development has largely focused on PARPs and PARG, no potent and selective inhibitors for ARH3 are currently available. We optimized a FRET-based competition assay for ARH3 and carried out high-throughput screening of small-molecule inhibitors. One hit compound, 1, with a potency of 22 muM was discovered, and through structure-activity relationship studies and synthesis, we improved its potency 10-fold to 2 muM (compound 27, MDOLL-0286). We demonstrate that the compound inhibits ARH3's poly-ADP-ribose hydrolytic activity on cellular substrates. Intriguingly, it does not effectively inhibit the hydrolysis of mono-ADP-ribosylation from natural protein substrates. This is despite the fact that the cocrystal structure of compound 1 bound to ARH3 reveals its overlap with the enzyme's ADP-ribose binding site, agreeing with the competition in the FRET assay. The first experimental ARH3 inhibitor complex provides a valuable starting point for developing more potent chemical probes to study DNA damage response mechanisms in the future. | ||
| - | + | Discovery and Structural Optimization of 2-Hydrazinopyrimidin-4-one Analogs Inhibiting Human ADP-Ribosylhydrolase ARH3.,Parviainen TAO, Duong MTH, Paakkonen J, Burdova K, Kuttichova B, Hanzlikova H, Lehtio L, Heiskanen JP ACS Chem Biol. 2025 Sep 15. doi: 10.1021/acschembio.5c00461. PMID:40952342<ref>PMID:40952342</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Lehtio | + | <div class="pdbe-citations 9rfe" style="background-color:#fffaf0;"></div> |
| - | [[Category: Paakkonen | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Lehtio L]] | ||
| + | [[Category: Paakkonen J]] | ||
Current revision
Human ADP-ribosylhydrolase 3 (ARH3) in complex with an inhibitor
| |||||||||||
