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5ha9

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Revision as of 07:28, 9 August 2023

Crystal structure-based design and disovery of a novel PARP1 antiagonist (BL-PA10) that induces apoptosis and inhibits metastasis in triple negative breast cancer

Structural highlights

5ha9 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 4.01Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PARP1_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. Mediates the poly(ADP-ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors. Lead optimization result in the identification of compound OL-1 (2-(11-(3-(dimethylamino)propylidene)-6,11- dihydrodibenzo[b,e]oxepin )-2-yl)acetohydrazide), which has a novel chemical scaffold and unique binding interaction with PARP1 protein. OL-1 demonstrated excellent potency (inhibiting PARP1 enzyme activity with IC50 = 0.079 muM), as well as inhibiting PARP-modulated PARylation and cell proliferation in MDA-MB-436 cells (BRAC1 mutation). In addition, OL-1 also inhibited cell migration that closely related to cancer metastasis and displayed remarkable anti-tumor efficacy in MDA-MB-436 xenograft model without apparent toxicities. These findings highlight a new small-molecule PAPR1 inhibitor (OL-1) that has the potential to impact future TNBC therapy.

Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer.,Fu L, Wang S, Wang X, Wang P, Zheng Y, Yao D, Guo M, Zhang L, Ouyang L Sci Rep. 2016 Dec 5;6(1):3. doi: 10.1038/s41598-016-0007-2. PMID:28442756^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Maruyama T, Nara K, Yoshikawa H, Suzuki N. Txk, a member of the non-receptor tyrosine kinase of the Tec family, forms a complex with poly(ADP-ribose) polymerase 1 and elongation factor 1alpha and regulates interferon-gamma gene transcription in Th1 cells. Clin Exp Immunol. 2007 Jan;147(1):164-75. PMID:17177976 doi:10.1111/j.1365-2249.2006.03249.x
↑ Ahel I, Ahel D, Matsusaka T, Clark AJ, Pines J, Boulton SJ, West SC. Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins. Nature. 2008 Jan 3;451(7174):81-5. doi: 10.1038/nature06420. PMID:18172500 doi:10.1038/nature06420
↑ Reinemund J, Seidel K, Steckelings UM, Zaade D, Klare S, Rompe F, Katerbaum M, Schacherl J, Li Y, Menk M, Schefe JH, Goldin-Lang P, Szabo C, Olah G, Unger T, Funke-Kaiser H. Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes. Biochem Pharmacol. 2009 Jun 15;77(12):1795-805. doi: 10.1016/j.bcp.2009.02.025., Epub 2009 Mar 19. PMID:19344625 doi:10.1016/j.bcp.2009.02.025
↑ Ahel D, Horejsi Z, Wiechens N, Polo SE, Garcia-Wilson E, Ahel I, Flynn H, Skehel M, West SC, Jackson SP, Owen-Hughes T, Boulton SJ. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science. 2009 Sep 4;325(5945):1240-3. doi: 10.1126/science.1177321. Epub 2009 Aug, 6. PMID:19661379 doi:10.1126/science.1177321
↑ Fu L, Wang S, Wang X, Wang P, Zheng Y, Yao D, Guo M, Zhang L, Ouyang L. Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer. Sci Rep. 2016 Dec 5;6(1):3. doi: 10.1038/s41598-016-0007-2. PMID:28442756 doi:http://dx.doi.org/10.1038/s41598-016-0007-2

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5ha9"

@@ Line 1: / Line 1: @@
 ==Crystal structure-based design and disovery of a novel PARP1 antiagonist (BL-PA10) that induces apoptosis and inhibits metastasis in triple negative breast cancer==
-<StructureSection load='5ha9' size='340' side='right' caption='[[5ha9]], [[Resolution|resolution]] 4.01&Aring;' scene=''>
+<StructureSection load='5ha9' size='340' side='right'caption='[[5ha9]], [[Resolution|resolution]] 4.01&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ha9]] is a 2 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=5HA9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HA9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ha9]] 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=5HA9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HA9 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TP0:AMITRIPTYLINE'>TP0</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]] 4.01&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PARP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TP0:AMITRIPTYLINE'>TP0</scene></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>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ha9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ha9 OCA], [https://pdbe.org/5ha9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ha9 RCSB], [https://www.ebi.ac.uk/pdbsum/5ha9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ha9 ProSAT]</span></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=5ha9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ha9 OCA], [http://pdbe.org/5ha9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ha9 RCSB], [http://www.ebi.ac.uk/pdbsum/5ha9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ha9 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/PARP1_HUMAN PARP1_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. Mediates the poly(ADP-ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production.<ref>PMID:17177976</ref> <ref>PMID:18172500</ref> <ref>PMID:19344625</ref> <ref>PMID:19661379</ref>
+[https://www.uniprot.org/uniprot/PARP1_HUMAN PARP1_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. Mediates the poly(ADP-ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production.<ref>PMID:17177976</ref> <ref>PMID:18172500</ref> <ref>PMID:19344625</ref> <ref>PMID:19661379</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 21: @@
 ==See Also==
-*[[Poly (ADP-ribose) polymerase|Poly (ADP-ribose) polymerase]]
+*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Fu, L]]
+[[Category: Large Structures]]
-[[Category: Ouyang, L]]
+[[Category: Fu L]]
-[[Category: Peng, H]]
+[[Category: Ouyang L]]
-[[Category: Zhang, L]]
+[[Category: Peng H]]
-[[Category: Inhibitor]]
+[[Category: Zhang L]]
-[[Category: Transferase-transferase inhibitor complex]]

5ha9

From Proteopedia

Revision as of 07:28, 9 August 2023

Crystal structure-based design and disovery of a novel PARP1 antiagonist (BL-PA10) that induces apoptosis and inhibits metastasis in triple negative breast cancer

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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