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- PDB-6hmk: POLYADPRIBOSYL GLYCOHYDROLASE IN COMPLEX WITH PDD00016690 -

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Basic information

Entry
Database: PDB / ID: 6hmk
TitlePOLYADPRIBOSYL GLYCOHYDROLASE IN COMPLEX WITH PDD00016690
ComponentsPoly(ADP-ribose) glycohydrolase
KeywordsHYDROLASE / COMPETITIVE INHIBITOR / PARG
Function / homology
Function and homology information


nucleotide-sugar metabolic process / poly(ADP-ribose) glycohydrolase / poly(ADP-ribose) glycohydrolase activity / ATP generation from poly-ADP-D-ribose / POLB-Dependent Long Patch Base Excision Repair / regulation of DNA repair / base-excision repair, gap-filling / carbohydrate metabolic process / nuclear body / mitochondrial matrix ...nucleotide-sugar metabolic process / poly(ADP-ribose) glycohydrolase / poly(ADP-ribose) glycohydrolase activity / ATP generation from poly-ADP-D-ribose / POLB-Dependent Long Patch Base Excision Repair / regulation of DNA repair / base-excision repair, gap-filling / carbohydrate metabolic process / nuclear body / mitochondrial matrix / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
: / Poly (ADP-ribose) glycohydrolase (PARG), helical domain / Poly (ADP-ribose) glycohydrolase (PARG), catalytic domain / Poly(ADP-ribose) glycohydrolase / Poly (ADP-ribose) glycohydrolase (PARG), Macro domain fold
Similarity search - Domain/homology
Chem-7JC / Poly(ADP-ribose) glycohydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.06 Å
AuthorsTucker, J.A. / Barkauskaite, E.
CitationJournal: J.Med.Chem. / Year: 2018
Title: Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides.
Authors: Waszkowycz, B. / Smith, K.M. / McGonagle, A.E. / Jordan, A.M. / Acton, B. / Fairweather, E.E. / Griffiths, L.A. / Hamilton, N.M. / Hamilton, N.S. / Hitchin, J.R. / Hutton, C.P. / James, D.I. ...Authors: Waszkowycz, B. / Smith, K.M. / McGonagle, A.E. / Jordan, A.M. / Acton, B. / Fairweather, E.E. / Griffiths, L.A. / Hamilton, N.M. / Hamilton, N.S. / Hitchin, J.R. / Hutton, C.P. / James, D.I. / Jones, C.D. / Jones, S. / Mould, D.P. / Small, H.F. / Stowell, A.I.J. / Tucker, J.A. / Waddell, I.D. / Ogilvie, D.J.
History
DepositionSep 12, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 14, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 21, 2018Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Apr 24, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.3Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Poly(ADP-ribose) glycohydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,1509
Polymers61,0961
Non-polymers1,0538
Water8,071448
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1180 Å2
ΔGint-30 kcal/mol
Surface area21030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.090, 90.110, 95.500
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Poly(ADP-ribose) glycohydrolase


Mass: 61096.492 Da / Num. of mol.: 1 / Mutation: K616A, Q617A, K618A, E688A, K689A, K690A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARG / Plasmid: pET28b / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): GOLD
References: UniProt: Q86W56, poly(ADP-ribose) glycohydrolase

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Non-polymers , 5 types, 456 molecules

#2: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-7JC / 1-methyl-~{N}-(1-methylcyclopropyl)-3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-bis(oxidanylidene)quinazoline-6-sulfonamide


Mass: 420.506 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20N4O4S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 448 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.47 Å3/Da / Density % sol: 50.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 750 nL purified protein at 7.5 mg/mL in 50 mM HEPES, pH 7.0, 150 mM NaCl, 2 mM DTT was mixed with 250 nL of seed stock and 1000 nL of a precipitant consisting of 18-23 % (w/v) PEG-3350, 0.2 ...Details: 750 nL purified protein at 7.5 mg/mL in 50 mM HEPES, pH 7.0, 150 mM NaCl, 2 mM DTT was mixed with 250 nL of seed stock and 1000 nL of a precipitant consisting of 18-23 % (w/v) PEG-3350, 0.2 M ammonium sulphate, 0.1 M PCTP pH 7.5. Seed stock was prepared using a Seed BeadTM (Hampton Research) from a co-crystal of GS-PARG(448-976 [K617A, Q618A, K619A, E688A, K689A, K690A]) with ADP-ribose, with co-crystallisation mother liquor (19 % (w/v) PEG-3350, 0.2 M ammonium sulphate, 0.1 M PCTP pH 7.5) as the stabilising solution. The final volume of the seed stock was 100 microL.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 11, 2013
RadiationMonochromator: Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.06→34.83 Å / Num. obs: 36540 / % possible obs: 100 % / Redundancy: 5.9 % / Biso Wilson estimate: 27.39 Å2 / Rmerge(I) obs: 0.092 / Net I/σ(I): 11.4
Reflection shellResolution: 2.06→2.16 Å / Redundancy: 6.1 % / Rmerge(I) obs: 0.597 / Mean I/σ(I) obs: 3.2 / Num. measured obs: 2939 / % possible all: 100

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Processing

Software
NameClassification
XDSdata reduction
Aimlessdata scaling
BUSTERrefinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4A0D

4a0d


Resolution: 2.06→28.77 Å / SU R Cruickshank DPI: 0.16 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.175 / SU Rfree Blow DPI: 0.143 / SU Rfree Cruickshank DPI: 0.143
RfactorNum. reflection% reflectionSelection details
Rfree0.1888 1823 5.01 %RANDOM
Rwork0.1536 ---
obs0.1554 36386 99.7 %-
Displacement parametersBiso mean: 33.03 Å2
Baniso -1Baniso -2Baniso -3
1-6.2142 Å20 Å20 Å2
2--3.0208 Å20 Å2
3----9.235 Å2
Refine analyzeLuzzati coordinate error obs: 0.211 Å
Refinement stepCycle: LAST / Resolution: 2.06→28.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4028 0 62 448 4538
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONBOND ANGLES0.965850HARMONIC2
X-RAY DIFFRACTIONBOND LENGTHS0.014286HARMONIC2
X-RAY DIFFRACTIONPEPTIDE OMEGA TORSION ANGLES3.431458SINUSOIDAL2
X-RAY DIFFRACTIONOTHER TORSION ANGLES16.45SINUSOIDAL2
LS refinement shellResolution: 2.06→2.12 Å
RfactorNum. reflection% reflection
Rfree0.2213 130 4.42 %
Rwork0.1862 2809 -
obs--99.7 %

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