| Structural highlights
4l7n is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Related: | 4gv0, 4gv2, 4gv4, 4l6z, 4l70, 4l7l |
| Gene: | ADPRT3, ADPRTL3, PARP3 (HUMAN) |
| Activity: | NAD(+) ADP-ribosyltransferase, with EC number 2.4.2.30 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Function
[PARP3_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. May link the DNA damage surveillance network to the mitotic fidelity checkpoint. Negatively influences the G1/S cell cycle progression without interfering with centrosome duplication. Binds DNA. May be involved in the regulation of PRC2 and PRC3 complex-dependent gene silencing.[1]
Publication Abstract from PubMed
The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of 55 compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.
Chemical probes to study ADP-ribosylation: synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3.,Lindgren AE, Karlberg T, Ekblad T, Spjut S, Thorsell AG, Andersson CD, Nhan TT, Hellsten V, Weigelt J, Linusson A, Schuler H, Elofsson M J Med Chem. 2013 Dec 12;56(23):9556-68. doi: 10.1021/jm401394u. Epub 2013 Nov 22. PMID:24188023[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Rouleau M, McDonald D, Gagne P, Ouellet ME, Droit A, Hunter JM, Dutertre S, Prigent C, Hendzel MJ, Poirier GG. PARP-3 associates with polycomb group bodies and with components of the DNA damage repair machinery. J Cell Biochem. 2007 Feb 1;100(2):385-401. PMID:16924674 doi:10.1002/jcb.21051
- ↑ Lindgren AE, Karlberg T, Ekblad T, Spjut S, Thorsell AG, Andersson CD, Nhan TT, Hellsten V, Weigelt J, Linusson A, Schuler H, Elofsson M. Chemical probes to study ADP-ribosylation: synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3. J Med Chem. 2013 Dec 12;56(23):9556-68. doi: 10.1021/jm401394u. Epub 2013 Nov 22. PMID:24188023 doi:http://dx.doi.org/10.1021/jm401394u
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