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- PDB-8gd7: Loop Deleted DNA Polymerase Theta Polymerase Domain in Complex wi... -

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Basic information

Entry
Database: PDB / ID: 8gd7
TitleLoop Deleted DNA Polymerase Theta Polymerase Domain in Complex with Double Strand DNA Overhang and Inhibitor
Components
  • DNA Primer
  • DNA Template
  • DNA polymerase theta
KeywordsDNA BINDING PROTEIN/DNA / DNA Polymerase Theta / inhibitor / DNA BINDING PROTEIN / DNA BINDING PROTEIN-DNA complex
Function / homology
Function and homology information


single-stranded DNA endodeoxyribonuclease activity / HDR through MMEJ (alt-NHEJ) / single-stranded DNA helicase activity / double-strand break repair via alternative nonhomologous end joining / replication fork processing / site of DNA damage / 5'-deoxyribose-5-phosphate lyase activity / somatic hypermutation of immunoglobulin genes / negative regulation of double-strand break repair via homologous recombination / error-prone translesion synthesis ...single-stranded DNA endodeoxyribonuclease activity / HDR through MMEJ (alt-NHEJ) / single-stranded DNA helicase activity / double-strand break repair via alternative nonhomologous end joining / replication fork processing / site of DNA damage / 5'-deoxyribose-5-phosphate lyase activity / somatic hypermutation of immunoglobulin genes / negative regulation of double-strand break repair via homologous recombination / error-prone translesion synthesis / DNA helicase activity / base-excision repair / protein homooligomerization / RNA-directed DNA polymerase / RNA-directed DNA polymerase activity / double-strand break repair / site of double-strand break / DNA helicase / damaged DNA binding / DNA-directed DNA polymerase / DNA-directed DNA polymerase activity / DNA repair / DNA damage response / chromatin binding / Golgi apparatus / magnesium ion binding / ATP hydrolysis activity / nucleoplasm / ATP binding / identical protein binding / cytosol
Similarity search - Function
DNA polymerase theta-like, helix-turn-helix domain / : / Helix-turn-helix domain / DNA_pol_Q helicase like region helical domain / DNA polymerase A / DNA polymerase family A / DNA-directed DNA polymerase, family A, conserved site / DNA polymerase family A signature. / DNA-directed DNA polymerase, family A, palm domain / DNA polymerase A domain ...DNA polymerase theta-like, helix-turn-helix domain / : / Helix-turn-helix domain / DNA_pol_Q helicase like region helical domain / DNA polymerase A / DNA polymerase family A / DNA-directed DNA polymerase, family A, conserved site / DNA polymerase family A signature. / DNA-directed DNA polymerase, family A, palm domain / DNA polymerase A domain / DEAD/DEAH box helicase / DEAD/DEAH box helicase domain / Helicase conserved C-terminal domain / helicase superfamily c-terminal domain / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Ribonuclease H superfamily / Ribonuclease H-like superfamily / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
2'-3'-DIDEOXYGUANOSINE-5'-TRIPHOSPHATE / : / DNA / DNA (> 10) / DNA polymerase theta
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.24 Å
AuthorsFried, W.A. / Chen, X.S. / Li, S.X.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM130889 United States
CitationJournal: Nat Commun / Year: 2024
Title: Discovery of a small-molecule inhibitor that traps Pol theta on DNA and synergizes with PARP inhibitors.
Authors: Fried, W. / Tyagi, M. / Minakhin, L. / Chandramouly, G. / Tredinnick, T. / Ramanjulu, M. / Auerbacher, W. / Calbert, M. / Rusanov, T. / Hoang, T. / Borisonnik, N. / Betsch, R. / Krais, J.J. ...Authors: Fried, W. / Tyagi, M. / Minakhin, L. / Chandramouly, G. / Tredinnick, T. / Ramanjulu, M. / Auerbacher, W. / Calbert, M. / Rusanov, T. / Hoang, T. / Borisonnik, N. / Betsch, R. / Krais, J.J. / Wang, Y. / Vekariya, U.M. / Gordon, J. / Morton, G. / Kent, T. / Skorski, T. / Johnson, N. / Childers, W. / Chen, X.S. / Pomerantz, R.T.
History
DepositionMar 3, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA polymerase theta
E: DNA Template
F: DNA Primer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,2246
Polymers84,2293
Non-polymers9953
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5100 Å2
ΔGint-19 kcal/mol
Surface area30160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)171.433, 171.433, 63.167
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Space group name HallP312"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: x-y,-y,-z+2/3
#5: -x,-x+y,-z+1/3
#6: y,x,-z

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Components

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Protein , 1 types, 1 molecules A

#1: Protein DNA polymerase theta / DNA polymerase eta


Mass: 72589.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: loop deleted polymerase domain / Source: (gene. exp.) Homo sapiens (human) / Gene: POLQ / Production host: Escherichia coli (E. coli) / References: UniProt: O75417, DNA-directed DNA polymerase

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DNA chain , 2 types, 2 molecules EF

#2: DNA chain DNA Template


Mass: 7372.730 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: DNA chain DNA Primer


Mass: 4266.768 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 3 types, 3 molecules

#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-DG3 / 2'-3'-DIDEOXYGUANOSINE-5'-TRIPHOSPHATE


Mass: 491.182 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O12P3
#6: Chemical ChemComp-Z5X / 2-(3-methyl-2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl (4-fluorophenyl)methylcarbamate


Mass: 479.348 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H16F7N3O3 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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: 3.15 Å3/Da / Density % sol: 60.9 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.24 M Sodium citrate, 18% (w/v) PEG 3350, 0.1 M Bis Tris Propane pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cold nitrogen gas stream / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 20, 2022
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 3.24→49.49 Å / Num. obs: 16950 / % possible obs: 98.4 % / Redundancy: 17.4 % / Biso Wilson estimate: 101.8 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.264 / Rpim(I) all: 0.063 / Rrim(I) all: 0.272 / Net I/av σ(I): 7.9 / Net I/σ(I): 7.9
Reflection shellResolution: 3.24→3.3 Å / Redundancy: 9.6 % / Rmerge(I) obs: 2.411 / Mean I/σ(I) obs: 1 / Num. unique obs: 751 / CC1/2: 0.408 / Rpim(I) all: 0.704 / Rrim(I) all: 2.521 / % possible all: 85.3

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHASERphasing
Cootmodel building
HKL-2000v722data scaling
HKL-2000v722data reduction
JBluIce-EPICSdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.24→42.86 Å / SU ML: 0.3978 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 30.8006
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.244 1688 9.96 %
Rwork0.2281 15255 -
obs0.2297 16943 98.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 121.76 Å2
Refinement stepCycle: LAST / Resolution: 3.24→42.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4983 467 64 0 5514
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00245665
X-RAY DIFFRACTIONf_angle_d0.51147749
X-RAY DIFFRACTIONf_chiral_restr0.0381857
X-RAY DIFFRACTIONf_plane_restr0.0044909
X-RAY DIFFRACTIONf_dihedral_angle_d15.7592906
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.24-3.340.36371260.34721125X-RAY DIFFRACTION86.81
3.34-3.440.33841350.34691222X-RAY DIFFRACTION96.31
3.44-3.570.34981390.32051255X-RAY DIFFRACTION98.24
3.57-3.710.29341430.28851296X-RAY DIFFRACTION99.79
3.71-3.880.2581400.25681254X-RAY DIFFRACTION100
3.88-4.080.25631400.24481275X-RAY DIFFRACTION100
4.08-4.340.22671400.21691292X-RAY DIFFRACTION100
4.34-4.670.22281450.20291284X-RAY DIFFRACTION99.93
4.67-5.140.20361430.20661287X-RAY DIFFRACTION100
5.14-5.880.24191390.23511307X-RAY DIFFRACTION100
5.88-7.40.2791480.24051300X-RAY DIFFRACTION100
7.41-42.860.19851500.17841358X-RAY DIFFRACTION99.87
Refinement TLS params.Method: refined / Origin x: 51.4540360937 Å / Origin y: 32.2835829822 Å / Origin z: 6.67141409022 Å
111213212223313233
T0.611850303939 Å20.0137497825462 Å2-0.065928364942 Å2-0.737962388144 Å20.170973480477 Å2--1.00743043235 Å2
L2.63132132778 °20.933347530519 °2-0.194625843052 °2-1.89007702502 °20.0509802432538 °2--0.687486691474 °2
S-0.0315324919353 Å °0.134716490582 Å °0.00995190258823 Å °-0.159359770007 Å °0.225460633542 Å °0.142410399584 Å °-0.18004809049 Å °-0.0891886122379 Å °-0.198126896792 Å °
Refinement TLS groupSelection details: all

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