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- PDB-8cvq: Crystal structure of TDP1 complexed with compound XZ761 -

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Basic information

Entry
Database: PDB / ID: 8cvq
TitleCrystal structure of TDP1 complexed with compound XZ761
ComponentsTyrosyl-DNA phosphodiesterase 1
KeywordsHYDROLASE / phosphodiesterase / DNA BINDING PROTEIN
Function / homology
Function and homology information


3'-tyrosyl-DNA phosphodiesterase activity / single strand break repair / Hydrolases; Acting on ester bonds; Phosphoric-diester hydrolases / exonuclease activity / Nonhomologous End-Joining (NHEJ) / double-strand break repair / single-stranded DNA binding / double-stranded DNA binding / intracellular membrane-bounded organelle / DNA repair ...3'-tyrosyl-DNA phosphodiesterase activity / single strand break repair / Hydrolases; Acting on ester bonds; Phosphoric-diester hydrolases / exonuclease activity / Nonhomologous End-Joining (NHEJ) / double-strand break repair / single-stranded DNA binding / double-stranded DNA binding / intracellular membrane-bounded organelle / DNA repair / nucleoplasm / nucleus / plasma membrane / cytoplasm
Similarity search - Function
Tyrosyl-DNA phosphodiesterase I / Tyrosyl-DNA phosphodiesterase
Similarity search - Domain/homology
Chem-OYH / Tyrosyl-DNA phosphodiesterase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsLountos, G.T. / Zhao, X.Z. / Wang, W. / Kiselev, E. / Tropea, J.E. / Needle, D. / Pommier, Y. / Burke, T.R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Rsc Chem Biol / Year: 2023
Title: Identification of multidentate tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors that simultaneously access the DNA, protein and catalytic-binding sites by oxime diversification.
Authors: Zhao, X.Z. / Wang, W. / Lountos, G.T. / Kiselev, E. / Tropea, J.E. / Needle, D. / Pommier, Y. / Burke Jr., T.R.
History
DepositionMay 18, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 12, 2023Provider: repository / Type: Initial release
Revision 1.1May 31, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 25, 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

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Assembly

Deposited unit
A: Tyrosyl-DNA phosphodiesterase 1
B: Tyrosyl-DNA phosphodiesterase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,00513
Polymers104,2532
Non-polymers1,75211
Water14,286793
1
A: Tyrosyl-DNA phosphodiesterase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,9716
Polymers52,1261
Non-polymers8455
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosyl-DNA phosphodiesterase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,0337
Polymers52,1261
Non-polymers9076
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.795, 105.012, 192.897
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Tyrosyl-DNA phosphodiesterase 1 / Tyr-DNA phosphodiesterase 1


Mass: 52126.336 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TDP1 / Details (production host): pDN2454 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9NUW8, Hydrolases; Acting on ester bonds; Phosphoric-diester hydrolases
#2: Chemical ChemComp-OYH / 4-{[(4S)-2,7-diphenylimidazo[1,2-a]pyridin-3-yl]amino}benzene-1,2-dicarboxylic acid


Mass: 449.457 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H19N3O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MPO / 3[N-MORPHOLINO]PROPANE SULFONIC ACID


Mass: 209.263 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H15NO4S / Comment: pH buffer*YM
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 793 / Source method: isolated from a natural source / Formula: H2O
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: 2.42 Å3/Da / Density % sol: 49.15 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1 M MOPS/HEPES-Na pH 7.5, 10% (w/v) PEG 8000, 20% (v/v) ethylene glycol, 0.03 M sodium fluoride, 0.03 M sodium bromide and 0.03 M sodium iodide

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Dec 17, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.65→50 Å / Num. obs: 122293 / % possible obs: 100 % / Redundancy: 7.3 % / CC1/2: 0.994 / Rmerge(I) obs: 0.11 / Rpim(I) all: 0.044 / Net I/σ(I): 20.2
Reflection shellResolution: 1.65→1.68 Å / Rmerge(I) obs: 0.724 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 6022 / CC1/2: 0.853 / Rpim(I) all: 0.319 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DHU

6dhu


Resolution: 1.65→46.115 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 18.49 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.194 6086 4.98 %
Rwork0.1666 116207 -
obs0.168 122293 99.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 89.96 Å2 / Biso mean: 23.7898 Å2 / Biso min: 7.03 Å2
Refinement stepCycle: final / Resolution: 1.65→46.115 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7005 0 122 793 7920
Biso mean--27.25 35.18 -
Num. residues----873
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.6502-1.6690.2661940.2414363294
1.669-1.68860.26841990.22943817100
1.6886-1.70920.25422140.21923842100
1.7092-1.73090.2232100.20393822100
1.7309-1.75360.25591880.19073812100
1.7536-1.77770.22842250.18583872100
1.7777-1.80310.21742040.17923762100
1.8031-1.830.23942030.17963860100
1.83-1.85860.19632010.16673824100
1.8586-1.8890.19421960.16563855100
1.889-1.92160.22161950.18053885100
1.9216-1.95660.23022080.17353806100
1.9566-1.99420.20312270.17063854100
1.9942-2.03490.17121810.15213850100
2.0349-2.07910.20422020.15723879100
2.0791-2.12750.20521780.15793865100
2.1275-2.18070.18551910.15343864100
2.1807-2.23970.20362130.15733850100
2.2397-2.30560.18532170.16913838100
2.3056-2.380.19191890.15983926100
2.38-2.4650.18911860.16053877100
2.465-2.56370.18011940.16763877100
2.5637-2.68040.18622170.16463900100
2.6804-2.82170.19522090.16463892100
2.8217-2.99850.20372150.17223891100
2.9985-3.22990.1882210.1693899100
3.2299-3.55480.17321900.15963982100
3.5548-4.0690.1882230.1543936100
4.069-5.12540.15351950.14354018100
5.1254-46.10.19632010.18374220100
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)
11.3827-0.18650.17930.7849-0.19831.2287-0.0557-0.17230.09060.06170.0350.0838-0.0663-0.11590.01620.11070.0242-0.00250.0916-0.00930.11321.58930.5143-35.5156
21.1105-0.2410.30990.5536-0.16561.27320.02550.094-0.0701-0.0713-0.02820.01770.11670.01140.0170.0931-0.01910.00010.048-0.00350.11359.9386-9.7912-49.3214
31.03820.09380.28420.26850.08171.18210.0306-0.0506-0.03630.0357-0.0278-0.01030.12660.1110.00660.10620.0109-0.00340.07090.01020.134519.3144-13.1675-38.6389
41.2902-0.15170.5080.7524-0.19932.4794-0.0390.24140.1334-0.0474-0.1058-0.1453-0.18860.49530.06130.1168-0.0437-0.00010.22720.0780.156313.54378.6178-84.5683
50.9820.02870.17180.6922-0.09482.07020.0342-0.1067-0.22680.00310.00960.0190.6578-0.2707-0.02060.2492-0.04380.01350.18330.02510.1767-2.0169-11.0985-84.4772
60.73370.11130.40250.3102-0.28792.54280.01910.0684-0.0455-0.0507-0.01330.00720.2346-0.2694-0.01460.1154-0.01170.01030.16950.00820.128-4.0822-3.0306-91.9405
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 162 through 285 )A162 - 285
2X-RAY DIFFRACTION2chain 'A' and (resid 286 through 452 )A286 - 452
3X-RAY DIFFRACTION3chain 'A' and (resid 453 through 607 )A453 - 607
4X-RAY DIFFRACTION4chain 'B' and (resid 162 through 359 )B162 - 359
5X-RAY DIFFRACTION5chain 'B' and (resid 360 through 452 )B360 - 452
6X-RAY DIFFRACTION6chain 'B' and (resid 453 through 607 )B453 - 607

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