Sandbox Reserved 1098

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This Sandbox is Reserved from 25/11/2019, through 30/9/2020 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1091 through Sandbox Reserved 1115.

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6HMM

The is a human poly (ADP-ribose) glycohydrolase.It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.

This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies.

Catabolism of poly (ADP-ribose)

This protein has four principal domains on a : an A-domain, a catalytic domain and two substrate binding domains. The first 456 amino acids of the peptide chain form the . Then, from the 610th to the 795th amino acids the can be found. This catalytic domain can bind to other proteins with (the 726th and 727th amino acids). Next, is located from the 869th to the 874th amino acid. As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the . These amino acids are located on a helix and on a beta sheet. There is the amino acid distribution [1].

The protein folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific signature sequence.

In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the protein. This loop gives the ability to hydrolyze PAR. The . (PAR is represented here in pink).

Post-translational modifications

The protein is a complex composed of the poly (ADP-ribose) glycohydrolase (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either PCNA or NUDT5, this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free (of identification number on PDB: 7JB) that can bind to the creating the.

There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation ^[1].

Another post-translational modification concerning the is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds ^[2]. This allows the repair of single-strand breaks on DNA ^[3]. The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype PARP1, will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate and form PAR chains. These will recruit other repair proteins to the site. The role of is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished^[3].

The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the . This PDD00013907 should lead to the inhibition of , which is of interest in the search of novel cancer therapies ^[4].

Diseases and Treatment

Due to the function of the protein poly (ADP-ribose) glycohydrolase to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of results in the cessing of the cell cycle and the following cell death^[3]^[4]. Consequently, the inhibition of might be a solution on how to destroy tumor cells, for example.

The PAR protein is a potential target in drug discovery as there are no close homologues of . That’s why there has already been a lot of research concerning novel treatments.

The goal of searched therapeutics is to find a way to get the protein into a complex that is acting similar to the .Indeed the protein in complex with the anthraquinone does not work properly anymore [2], the described complex shows how an inhibited might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell^[4].

References

↑ Oberle C, Blattner C. Regulation of the DNA Damage Response to DSBs by Post-Translational Modifications. Curr Genomics. 2010 May;11(3):184-98. doi: 10.2174/138920210791110979. PMID:21037856 doi:http://dx.doi.org/10.2174/138920210791110979
↑ Slade D, Dunstan MS, Barkauskaite E, Weston R, Lafite P, Dixon N, Ahel M, Leys D, Ahel I. The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase. Nature. 2011 Sep 4. doi: 10.1038/nature10404. PMID:21892188 doi:10.1038/nature10404
↑ ^3.0 ^3.1 ^3.2 Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792. doi: 10.1021/acs.jmedchem.8b01407., Epub 2018 Nov 19. PMID:30403352 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01407
↑ Cite error: Invalid <ref> tag; no text was provided for refs named James_DI.2C_Smith_KM.2C_Jordan_AM.2C_Fairweather_EE.2C_Griffiths_LA.2C_Hamilton_NS.2C_Hitchin_JR.2C_Hutton_CP.2C_Jones_S.2C_Kelly_P.2C_McGonagle_AE.2C_Small_H.2C_Stowell_AI.2C_Tucker_J.2C_Waddell_ID.2C_Waszkowycz_B.2C_Ogilvie_DJ._First-in-Class_Chemical_Probes_against_Poly.28ADP-ribose.29_Glycohydrolase_.28PARG.29_Inhibit_DNA_Repair_with_Differential_Pharmacology_to_Olaparib._ACS_Chem_Biol._2016_Oct_12.

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1098"

@@ Line 6: / Line 6: @@
-=== Catabolism of poly (ADP-ribose) ===
+== Catabolism of poly (ADP-ribose) ==
-This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56].
+This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains.
-The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]
+The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid.
-As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.
+As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution [http://www.uniprot.org/uniprot/Q86W56].
 The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence.
@@ Line 17: / Line 17: @@
-=== Post-translational modifications ===
+== Post-translational modifications ==
-The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability.
+The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability.
 PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>.
@@ Line 29: / Line 29: @@
-=== Diseases and Treatment ===
+== Diseases and Treatment ==
 Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.

Sandbox Reserved 1098

From Proteopedia

Current revision

6HMM

Catabolism of poly (ADP-ribose)

Post-translational modifications

Diseases and Treatment

References

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