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- PDB-6hml: POLYADPRIBOSYL GLYCOSIDASE IN COMPLEX WITH PDD00017299 -

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Basic information

Entry
Database: PDB / ID: 6hml
TitlePOLYADPRIBOSYL GLYCOSIDASE IN COMPLEX WITH PDD00017299
ComponentsPoly(ADP-ribose) glycohydrolase
KeywordsHYDROLASE
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 / cytosol / cytoplasm
Similarity search - Function
Poly(ADP-ribose) glycohydrolase / Poly (ADP-ribose) glycohydrolase (PARG), catalytic domain / : / Poly (ADP-ribose) glycohydrolase (PARG), Macro domain fold / Poly (ADP-ribose) glycohydrolase (PARG), helical domain
Similarity search - Domain/homology
Chem-73L / Poly(ADP-ribose) glycohydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 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)62,31610
Polymers61,0961
Non-polymers1,2199
Water5,855325
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1840 Å2
ΔGint-19 kcal/mol
Surface area20840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.310, 90.190, 95.990
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 mutations introduced to improve crystallisation propoensity
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARG / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Gold
References: UniProt: Q86W56, poly(ADP-ribose) glycohydrolase

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Non-polymers , 5 types, 334 molecules

#2: Chemical ChemComp-73L / 1-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-6-[[(1-methylcyclopropyl)amino]-bis(oxidanyl)-$l^{4}-sulfanyl]-3-[(1-methylpyrazol-4-yl)methyl]quinazoline-2,4-dione


Mass: 516.636 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28N6O4S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


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


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 325 / 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: 2.52 Å3/Da / Density % sol: 51.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: Mix 750 nL purified protein at 7.5 mg per mL in 50mM HEPES, pH 7.0, 150 mM NaCl, 2mM DTT with 250 nL of seed stock and 1000 nL of a precipitant consisting of 18-23 percent PEG 3350, 0.2 M ...Details: Mix 750 nL purified protein at 7.5 mg per mL in 50mM HEPES, pH 7.0, 150 mM NaCl, 2mM DTT with 250 nL of seed stock and 1000 nL of a precipitant consisting of 18-23 percent PEG 3350, 0.2 M ammonium sulphate, 0.1 M PCTP pH 7.5. Seed stock was prepared using a Seed Bead from a co-crystal with ADP-ribose, with co-crystallisation mother liquor (19 percent PEG 3350, 0.2 M ammonium sulphate, 0.1 M PCTP pH 7.5) as the stabilising solution

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.25→67.31 Å / Num. obs: 28396 / % possible obs: 99.9 % / Redundancy: 6.4 % / Biso Wilson estimate: 47.59 Å2 / Rmerge(I) obs: 0.083 / Net I/σ(I): 15.2
Reflection shellResolution: 2.25→2.31 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.758 / Mean I/σ(I) obs: 2.7 / % possible all: 99.9

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.5refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4A0D

4a0d


Resolution: 2.25→67.31 Å / SU R Cruickshank DPI: 0.239 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.261 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.175
RfactorNum. reflection% reflectionSelection details
Rfree0.1965 1429 5.04 %RANDOM
Rwork0.1622 ---
obs0.1639 28343 99.84 %-
Displacement parametersBiso mean: 47.88 Å2
Baniso -1Baniso -2Baniso -3
1-9.6477 Å20 Å20 Å2
2--0.5073 Å20 Å2
3----10.155 Å2
Refine analyzeLuzzati coordinate error obs: 0.228 Å
Refinement stepCycle: LAST / Resolution: 2.25→67.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4003 0 75 325 4403
Refine LS restraintsType: BOND LENGTHS / Dev ideal: 0.01 / Number: 4270 / Restraint function: HARMONIC / Weight: 2
LS refinement shellResolution: 2.25→2.33 Å
RfactorNum. reflection% reflection
Rfree0.2353 156 5.37 %
Rwork0.1864 2749 -
obs--99.84 %

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