6vkq

From Proteopedia

(Difference between revisions)

Revision as of 08:14, 11 October 2023

Crystal Structure of human PARP-1 CAT domain bound to inhibitor EB-47

Structural highlights

6vkq is a 4 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 2.9Å
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

The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.

Structural basis for allosteric PARP-1 retention on DNA breaks.,Zandarashvili L, Langelier MF, Velagapudi UK, Hancock MA, Steffen JD, Billur R, Hannan ZM, Wicks AJ, Krastev DB, Pettitt SJ, Lord CJ, Talele TT, Pascal JM, Black BE Science. 2020 Apr 3;368(6486). pii: 368/6486/eaax6367. doi:, 10.1126/science.aax6367. PMID:32241924^[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
↑ Zandarashvili L, Langelier MF, Velagapudi UK, Hancock MA, Steffen JD, Billur R, Hannan ZM, Wicks AJ, Krastev DB, Pettitt SJ, Lord CJ, Talele TT, Pascal JM, Black BE. Structural basis for allosteric PARP-1 retention on DNA breaks. Science. 2020 Apr 3;368(6486). pii: 368/6486/eaax6367. doi:, 10.1126/science.aax6367. PMID:32241924 doi:http://dx.doi.org/10.1126/science.aax6367

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/6vkq"

Categories: Homo sapiens | Large Structures | Pascal JM | Steffen JD

@@ Line 1: / Line 1: @@
 ==Crystal Structure of human PARP-1 CAT domain bound to inhibitor EB-47==
-<StructureSection load='6vkq' size='340' side='right'caption='[[6vkq]]' scene=''>
+<StructureSection load='6vkq' size='340' side='right'caption='[[6vkq]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VKQ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6VKQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6vkq]] is a 4 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=6VKQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VKQ FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6vkq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vkq OCA], [http://pdbe.org/6vkq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vkq RCSB], [http://www.ebi.ac.uk/pdbsum/6vkq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vkq ProSAT]</span></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]] 2.9&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <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'>[https://proteopedia.org/fgij/fg.htm?mol=6vkq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vkq OCA], [https://pdbe.org/6vkq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vkq RCSB], [https://www.ebi.ac.uk/pdbsum/6vkq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vkq ProSAT]</span></td></tr>
 </table>
+== Function ==
+[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 ==
+The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.
+Structural basis for allosteric PARP-1 retention on DNA breaks.,Zandarashvili L, Langelier MF, Velagapudi UK, Hancock MA, Steffen JD, Billur R, Hannan ZM, Wicks AJ, Krastev DB, Pettitt SJ, Lord CJ, Talele TT, Pascal JM, Black BE Science. 2020 Apr 3;368(6486). pii: 368/6486/eaax6367. doi:, 10.1126/science.aax6367. PMID:32241924<ref>PMID:32241924</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6vkq" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Pascal JM]]
 [[Category: Steffen JD]]

6vkq

From Proteopedia

Revision as of 08:14, 11 October 2023

Crystal Structure of human PARP-1 CAT domain bound to inhibitor EB-47

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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