Sandbox Reserved 1098

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=== Catabolism of poly (ADP-ribose) ===
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== Catabolism of poly (ADP-ribose) ==
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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].
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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.
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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]
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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.
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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.
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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].
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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.
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.
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).
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=== Post-translational modifications ===
 
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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.
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== Post-translational modifications ==
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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>.
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>.
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There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein 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 <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <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.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <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.">PMID: 27689388</ref>.
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There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.
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Another post-translational modification concerning the <scene name='82/829351/6hmm/2'>6HMM protein</scene> 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 <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <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.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 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 <scene name='82/829351/Parg/1'>PARG</scene> 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<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."/>.
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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 <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <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."/>.
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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 <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <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."/>.
 
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=== The mechanism ===
 
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As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site.
 
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The role of PARG 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<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."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>.
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== Diseases and Treatment ==
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== Diseases and Relevance ==
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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.
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Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG 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 PARG 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 PARG might be a solution on how to destroy tumor cells, for example.
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For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<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."/>, this protein provides a potential target in drug discovery.
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The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.
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As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<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."/>.
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The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<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."/>.

Current revision

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

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References

  1. ↑ 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
  2. ↑ 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. ↑ 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
  4. ↑ 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.
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