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- PDB-8e23: Human DNA polymerase theta in complex with allosteric inhibitor -

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Basic information

Entry
Database: PDB / ID: 8.0E+23
TitleHuman DNA polymerase theta in complex with allosteric inhibitor
Components
  • DNA (5'-D(*CP*GP*TP*CP*CP*AP*AP*TP*GP*AP*CP*AP*GP*CP*CP*GP*C)-3')
  • DNA (5'-D(*GP*C*GP*GP*CP*TP*GP*TP*CP*AP*TP*TP*G)-3')
  • DNA polymerase theta
KeywordsDNA BINDING PROTEIN/DNA / DNA polymerase theta / inhibitor / allosteric / complex / DNA BINDING PROTEIN / DNA BINDING PROTEIN-DNA complex
Function / homology
Function and homology information


double-strand break repair via alternative nonhomologous end joining / HDR through MMEJ (alt-NHEJ) / single-stranded DNA helicase activity / replication fork processing / site of DNA damage / mitochondrial nucleoid / 5'-deoxyribose-5-phosphate lyase activity / somatic hypermutation of immunoglobulin genes / error-prone translesion synthesis / negative regulation of double-strand break repair via homologous recombination ...double-strand break repair via alternative nonhomologous end joining / HDR through MMEJ (alt-NHEJ) / single-stranded DNA helicase activity / replication fork processing / site of DNA damage / mitochondrial nucleoid / 5'-deoxyribose-5-phosphate lyase activity / somatic hypermutation of immunoglobulin genes / error-prone translesion synthesis / negative regulation of double-strand break repair via homologous recombination / RNA-directed DNA polymerase activity / DNA helicase activity / base-excision repair / protein homooligomerization / RNA-directed DNA polymerase / double-strand break repair / site of double-strand break / DNA helicase / damaged DNA binding / DNA-directed DNA polymerase / DNA-directed DNA polymerase activity / chromatin extrusion motor activity / ATP-dependent H2AZ histone chaperone activity / ATP-dependent H3-H4 histone complex chaperone activity / cohesin loader activity / DNA clamp loader activity / DNA repair / DNA damage response / chromatin binding / Golgi apparatus / magnesium ion binding / ATP hydrolysis activity / nucleoplasm / ATP binding / identical protein binding / nucleus / cytosol
Similarity search - Function
: / DNA_pol_Q helicase like region helical domain / DNA polymerase theta-like, helix-turn-helix domain / Helix-turn-helix 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_pol_Q helicase like region helical domain / DNA polymerase theta-like, helix-turn-helix domain / Helix-turn-helix 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 domain / DEAD/DEAH box helicase / 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 / Chem-UAF / DNA / DNA (> 10) / DNA polymerase theta
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.59 Å
AuthorsMader, P. / Pau, V.P.T. / Sicheri, F.
Funding support Canada, 2items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)FDN 143277 Canada
Other private
Citation
Journal: J.Med.Chem. / Year: 2022
Title: Identification of RP-6685 , an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Pol theta.
Authors: Bubenik, M. / Mader, P. / Mochirian, P. / Vallee, F. / Clark, J. / Truchon, J.F. / Perryman, A.L. / Pau, V. / Kurinov, I. / Zahn, K.E. / Leclaire, M.E. / Papp, R. / Mathieu, M.C. / Hamel, M. ...Authors: Bubenik, M. / Mader, P. / Mochirian, P. / Vallee, F. / Clark, J. / Truchon, J.F. / Perryman, A.L. / Pau, V. / Kurinov, I. / Zahn, K.E. / Leclaire, M.E. / Papp, R. / Mathieu, M.C. / Hamel, M. / Duffy, N.M. / Godbout, C. / Casas-Selves, M. / Falgueyret, J.P. / Baruah, P.S. / Nicolas, O. / Stocco, R. / Poirier, H. / Martino, G. / Fortin, A.B. / Roulston, A. / Chefson, A. / Dorich, S. / St-Onge, M. / Patel, P. / Pellerin, C. / Ciblat, S. / Pinter, T. / Barabe, F. / El Bakkouri, M. / Parikh, P. / Gervais, C. / Sfeir, A. / Mamane, Y. / Morris, S.J. / Black, W.C. / Sicheri, F. / Gallant, M.
#1: Journal: J. Med. Chem. / Year: 2022
Title: Identification of Lead RP-6685: an orally bioavailable compound that inhibits the DNA polymerase activity of Pol Theta
Authors: Bubenik, M. / Mader, P. / Mochirian, P. / Vallee, F. / Clark, J. / Truchon, J.F. / Perryman, A.L. / Pau, V. / Kurinov, I. / Zahn, K.E. / Leclaire, M.E. / Papp, R. / Mathieu, M.C. / Hamel, M. ...Authors: Bubenik, M. / Mader, P. / Mochirian, P. / Vallee, F. / Clark, J. / Truchon, J.F. / Perryman, A.L. / Pau, V. / Kurinov, I. / Zahn, K.E. / Leclaire, M.E. / Papp, R. / Mathieu, M.C. / Hamel, M. / Duffy, N.M. / Godbout, C. / Casas-Selves, M. / Falgueyret, J.P. / Baruah, P.S. / Nicolas, O. / Stocco, R. / Poirier, H. / Martino, J. / Fortin, A.B. / Chefson, A. / Dorich, S. / St-Onge, M. / Patel, P. / Pellerin, C. / Ciblat, S. / Pinter, T. / Barabe, F. / El Bakkouri, M. / Parikh, P. / Gervais, C. / Mamane, Y. / Morris, S.J. / Black, C.W. / Sicheri, F. / Gallant, M.
History
DepositionAug 13, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 28, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 26, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA polymerase theta
B: DNA (5'-D(*CP*GP*TP*CP*CP*AP*AP*TP*GP*AP*CP*AP*GP*CP*CP*GP*C)-3')
C: DNA (5'-D(*GP*C*GP*GP*CP*TP*GP*TP*CP*AP*TP*TP*G)-3')
D: DNA polymerase theta
E: DNA (5'-D(*CP*GP*TP*CP*CP*AP*AP*TP*GP*AP*CP*AP*GP*CP*CP*GP*C)-3')
F: DNA (5'-D(*GP*C*GP*GP*CP*TP*GP*TP*CP*AP*TP*TP*G)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,08011
Polymers168,7126
Non-polymers1,3685
Water1,63991
1
A: DNA polymerase theta
B: DNA (5'-D(*CP*GP*TP*CP*CP*AP*AP*TP*GP*AP*CP*AP*GP*CP*CP*GP*C)-3')
C: DNA (5'-D(*GP*C*GP*GP*CP*TP*GP*TP*CP*AP*TP*TP*G)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,2096
Polymers84,3563
Non-polymers8533
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5440 Å2
ΔGint-23 kcal/mol
Surface area30230 Å2
MethodPISA
2
D: DNA polymerase theta
E: DNA (5'-D(*CP*GP*TP*CP*CP*AP*AP*TP*GP*AP*CP*AP*GP*CP*CP*GP*C)-3')
F: DNA (5'-D(*GP*C*GP*GP*CP*TP*GP*TP*CP*AP*TP*TP*G)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,8725
Polymers84,3563
Non-polymers5152
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4780 Å2
ΔGint-21 kcal/mol
Surface area31030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)246.850, 69.320, 147.430
Angle α, β, γ (deg.)90.000, 122.550, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 2 molecules AD

#1: Protein DNA polymerase theta / DNA polymerase eta


Mass: 75200.070 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: POLQ, POLH / Production host: Escherichia coli (E. coli) / References: UniProt: O75417, DNA-directed DNA polymerase

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DNA chain , 2 types, 4 molecules BECF

#2: DNA chain DNA (5'-D(*CP*GP*TP*CP*CP*AP*AP*TP*GP*AP*CP*AP*GP*CP*CP*GP*C)-3')


Mass: 5157.351 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: synthetic construct (others)
#3: DNA chain DNA (5'-D(*GP*C*GP*GP*CP*TP*GP*TP*CP*AP*TP*TP*G)-3')


Mass: 3998.595 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: synthetic construct (others)

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Non-polymers , 4 types, 96 molecules

#4: Chemical ChemComp-MG / MAGNESIUM ION


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


Mass: 491.182 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O12P3
#6: Chemical ChemComp-UAF / N-methyl-N-phenyl[(3aM)-3-(trifluoromethyl)cyclopenta[c]pyrazol-2(1H)-yl]ethanethioamide


Mass: 337.363 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H14F3N3S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 91 / Source method: isolated from a natural source / Formula: H2O

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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: 60.97 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 18.5 % PEG 3350; 0.2M diammonium tartrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-E / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 11, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.59→73.53 Å / Num. obs: 65106 / % possible obs: 93.7 % / Redundancy: 1.749 % / Biso Wilson estimate: 75.41 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.055 / Rrim(I) all: 0.076 / Χ2: 0.842 / Net I/σ(I): 8.45 / Num. measured all: 211027
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.59-2.741.750.8180.823409420760194800.4131.12993.8
2.74-2.931.7450.4541.593270319599187420.6930.62895.6
2.93-3.171.7560.2662.83094018278176180.8730.36896.4
3.17-3.471.7230.1315.642730616770158460.9630.18194.5
3.47-3.881.7810.0759.962534615206142330.9870.10593.6
3.88-4.481.7450.04715.422102713302120500.9940.06590.6
4.48-5.481.7060.03619.791722111300100940.9950.05189.3
5.48-7.741.7890.03121.7514599878781600.9960.04492.9
7.74-73.531.7450.02129.317791482144640.9980.0392.6

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4X0Q

4x0q


Resolution: 2.59→73.53 Å / SU ML: 0.44 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 31.84 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2947 1962 3.01 %
Rwork0.2468 63117 -
obs0.2482 65079 98.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 251.46 Å2 / Biso mean: 104.1841 Å2 / Biso min: 38.72 Å2
Refinement stepCycle: final / Resolution: 2.59→73.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9458 928 85 91 10562
Biso mean--93.04 76.73 -
Num. residues----1286
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.59-2.650.34871420.33914479462199
2.65-2.730.37121580.313945064664100
2.73-2.810.37291370.31184479461699
2.81-2.90.35421320.32664550468299
2.9-30.39721390.332244784617100
3-3.120.35521540.310345054659100
3.12-3.260.33981300.28114508463899
3.26-3.440.32661400.26714534467499
3.44-3.650.28991450.2744498464399
3.65-3.930.27951360.23664485462198
3.93-4.330.2971320.2214494462698
4.33-4.950.26441400.21444434457496
4.95-6.240.2851390.24254527466698
6.24-73.530.25561380.21594640477898
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.9271-0.46390.10110.82210.41260.87360.02240.60850.00410.11560.31250.0352-0.06580.61520.00150.6459-0.06360.10450.9609-0.15770.566357.5412-14.531115.9636
21.476-0.14680.25891.68340.59792.52150.13310.1685-0.05790.03740.0786-0.2444-0.09530.82990.00250.4878-0.03540.03120.6068-0.12360.48453.0734-10.629133.3181
30.16040.51070.16342.29581.06050.3381-0.0218-0.01060.17840.26130.2641-0.00110.13190.28780.00010.94740.06130.09770.52180.00070.63938.7329.635946.0987
41.5739-0.1167-0.26281.89440.16742.3942-0.0001-0.06480.01920.13430.06340.2604-0.1206-0.121200.4958-0.06740.07530.3218-0.00230.538431.56850.553447.6924
50.0603-0.30810.11930.6762-0.1480.1217-0.1126-0.11370.50640.0621-0.0115-0.6639-0.79160.65770.07090.9261-0.42060.12010.83-0.17070.995949.334814.929751.6439
60.6644-0.1530.31930.1813-0.23670.5023-0.0222-0.3063-0.3149-0.780.2974-2.5978-0.60551.74090.26941.0614-0.39960.4391.2906-0.2411.793150.044817.537346.3744
72.8810.84362.61270.58140.1832.3766-0.2793-0.830.4928-0.1501-0.08090.1225-0.3436-0.524-0.13330.44760.1593-0.01940.8449-0.33880.573124.0519-24.5351-14.8377
81.604-0.21320.6537-0.0127-0.03980.9054-0.8937-0.04791.3821-0.44850.19810.4933-1.0594-0.0596-0.85991.23370.148-0.77260.6244-0.13061.486314.3528-4.4239-33.1102
90.5637-0.5665-0.31460.3317-0.05991.9319-0.2591-0.73680.6094-0.4302-0.31251.2993-1.05760.0611-0.9691.03210.2738-0.49520.944-0.63431.275118.4084-2.8341-8.7648
101.29830.12470.4646-0.01740.02390.1696-0.8254-0.76990.5384-0.28790.38440.5422-0.5331-1.17920.03481.04370.0382-0.35181.0339-0.20491.24399.501-22.3324-32.7795
110.34390.7185-0.49661.5713-1.19670.907-0.1429-1.0388-0.3538-0.1870.0353-0.83020.1043-0.2683-0.25311.06810.6168-0.51741.6954-0.80211.71726.2908-22.1507-29.2406
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1824 through 1951 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 1952 through 2095 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 2096 through 2221 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 2222 through 2590 )A0
5X-RAY DIFFRACTION5chain 'B' and (resid 1 through 15 )B1 - 15
6X-RAY DIFFRACTION6chain 'C' and (resid 3 through 13 )C3 - 13
7X-RAY DIFFRACTION7chain 'D' and (resid 1821 through 2313 )D0
8X-RAY DIFFRACTION8chain 'D' and (resid 2314 through 2493 )D0
9X-RAY DIFFRACTION9chain 'D' and (resid 2494 through 2590 )D0
10X-RAY DIFFRACTION10chain 'E' and (resid 1 through 12 )E1 - 12
11X-RAY DIFFRACTION11chain 'F' and (resid 6 through 13 )F6 - 13

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