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| | ==Human artd3 (parp3) - catalytic domain in complex with inhibitor ME0368== | | ==Human artd3 (parp3) - catalytic domain in complex with inhibitor ME0368== |
| - | <StructureSection load='4l7l' size='340' side='right' caption='[[4l7l]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4l7l' size='340' side='right'caption='[[4l7l]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4l7l]] 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=4L7L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4L7L FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4l7l]] 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=4L7L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L7L FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1VA:N-[(2S)-1-HYDROXY-3-PHENYLPROPAN-2-YL]-3-(4-OXO-3,4-DIHYDROQUINAZOLIN-2-YL)PROPANAMIDE'>1VA</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gv0|4gv0]], [[4gv2|4gv2]], [[4gv4|4gv4]], [[4l6z|4l6z]], [[4l70|4l70]], [[4l7n|4l7n]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1VA:N-[(2S)-1-HYDROXY-3-PHENYLPROPAN-2-YL]-3-(4-OXO-3,4-DIHYDROQUINAZOLIN-2-YL)PROPANAMIDE'>1VA</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADPRT3, ADPRTL3, PARP3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4l7l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l7l OCA], [https://pdbe.org/4l7l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l7l RCSB], [https://www.ebi.ac.uk/pdbsum/4l7l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l7l ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/NAD(+)_ADP-ribosyltransferase NAD(+) ADP-ribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.30 2.4.2.30] </span></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=4l7l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l7l OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4l7l RCSB], [http://www.ebi.ac.uk/pdbsum/4l7l PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PARP3_HUMAN 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.<ref>PMID:16924674</ref> | + | [https://www.uniprot.org/uniprot/PARP3_HUMAN 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.<ref>PMID:16924674</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4l7l" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Poly (ADP-ribose) polymerase|Poly (ADP-ribose) polymerase]] | + | *[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Andersson, C D]] | + | [[Category: Large Structures]] |
| - | [[Category: Ekblad, T]] | + | [[Category: Andersson CD]] |
| - | [[Category: Elofsson, M]] | + | [[Category: Ekblad T]] |
| - | [[Category: Karlberg, T]] | + | [[Category: Elofsson M]] |
| - | [[Category: Lindgren, A E.G]] | + | [[Category: Karlberg T]] |
| - | [[Category: Linusson, A]] | + | [[Category: Lindgren AEG]] |
| - | [[Category: Schuler, H]] | + | [[Category: Linusson A]] |
| - | [[Category: Spjut, S]] | + | [[Category: Schuler H]] |
| - | [[Category: Thorsell, A G]] | + | [[Category: Spjut S]] |
| - | [[Category: Weigelt, J]] | + | [[Category: Thorsell AG]] |
| - | [[Category: Adp-ribosylation]]
| + | [[Category: Weigelt J]] |
| - | [[Category: Diphtheria toxin like adp-ribose transferase]]
| + | |
| - | [[Category: Transferase]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
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| Structural highlights
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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