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- PDB-8v0c: Structure of TDP1 catalytic domain complexed with compound IB06 -

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Basic information

Entry
Database: PDB / ID: 8v0c
TitleStructure of TDP1 catalytic domain complexed with compound IB06
ComponentsTyrosyl-DNA phosphodiesterase 1
KeywordsDNA BINDING PROTEIN / HYDROLASE/INHIBITOR / phosphodiesterase / drug target / cancer / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


3'-tyrosyl-DNA phosphodiesterase activity / Hydrolases; Acting on ester bonds; Phosphoric-diester hydrolases / single strand break repair / exonuclease activity / Nonhomologous End-Joining (NHEJ) / double-strand break repair / single-stranded DNA binding / double-stranded DNA binding / DNA repair / intracellular membrane-bounded organelle ...3'-tyrosyl-DNA phosphodiesterase activity / Hydrolases; Acting on ester bonds; Phosphoric-diester hydrolases / single strand break repair / exonuclease activity / Nonhomologous End-Joining (NHEJ) / double-strand break repair / single-stranded DNA binding / double-stranded DNA binding / DNA repair / intracellular membrane-bounded organelle / nucleoplasm / nucleus / plasma membrane / cytoplasm
Similarity search - Function
Tyrosyl-DNA phosphodiesterase I / Tyrosyl-DNA phosphodiesterase
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / : / Tyrosyl-DNA phosphodiesterase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.62 Å
AuthorsLountos, G.T. / Zhao, X.Z. / Barakat, I. / Wang, W. / Agama, K. / Al Mahmud, M.R. / Pommier, Y. / Burke Jr., T.R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: To Be Published
Title: Structures of TDP1 complexed with inhibitors
Authors: Lountos, G.T. / Zhao, X.Z. / Barakat, I. / Wang, W. / Agama, K. / Al Mahmud, M.R. / Pommier, Y. / Burke Jr., T.R.
History
DepositionNov 17, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)105,82015
Polymers104,2532
Non-polymers1,56813
Water12,989721
1
A: Tyrosyl-DNA phosphodiesterase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,0119
Polymers52,1261
Non-polymers8858
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosyl-DNA phosphodiesterase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,8096
Polymers52,1261
Non-polymers6835
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.020, 105.183, 193.625
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, 2 molecules AB

#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 / Plasmid: pDN2454 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9NUW8, Hydrolases; Acting on ester bonds; Phosphoric-diester hydrolases

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Non-polymers , 5 types, 734 molecules

#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-YE3 / (8M)-8-(2-{[2-(fluorosulfonyl)ethyl]amino}phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid


Mass: 390.386 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H15FN2O5S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 721 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.44 Å3/Da / Density % sol: 49.65 %
Crystal growTemperature: 293 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, 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-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 17, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.62→50 Å / Num. obs: 123313 / % possible obs: 94.4 % / Redundancy: 5.3 % / CC1/2: 0.998 / CC star: 1 / Rpim(I) all: 0.031 / Rsym value: 0.067 / Net I/σ(I): 20.6
Reflection shellResolution: 1.62→1.65 Å / Redundancy: 5.4 % / Mean I/σ(I) obs: 1.9 / Num. unique obs: 5958 / CC1/2: 0.802 / CC star: 0.943 / Rpim(I) all: 0.299 / Rsym value: 0.666 / % possible all: 92.5

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.62→45.172 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 18.75 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2031 2000 1.62 %
Rwork0.1717 --
obs0.1722 123227 94.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.62→45.172 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7017 0 104 721 7842
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0067752
X-RAY DIFFRACTIONf_angle_d0.86410588
X-RAY DIFFRACTIONf_dihedral_angle_d6.5476099
X-RAY DIFFRACTIONf_chiral_restr0.0551087
X-RAY DIFFRACTIONf_plane_restr0.0061351
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6201-1.66060.2431370.21798300X-RAY DIFFRACTION91
1.6606-1.70550.24131360.19778296X-RAY DIFFRACTION92
1.7055-1.75570.23211380.19528316X-RAY DIFFRACTION92
1.7557-1.81240.23761370.19138338X-RAY DIFFRACTION92
1.8124-1.87710.23191380.18128308X-RAY DIFFRACTION91
1.8771-1.95230.20591360.17898291X-RAY DIFFRACTION91
1.9523-2.04120.20621390.17418386X-RAY DIFFRACTION92
2.0412-2.14880.22351390.17348424X-RAY DIFFRACTION92
2.1488-2.28340.21871420.17188648X-RAY DIFFRACTION94
2.2834-2.45970.19661460.17188788X-RAY DIFFRACTION96
2.4597-2.70720.19621480.17729020X-RAY DIFFRACTION98
2.7072-3.09880.23421520.17849179X-RAY DIFFRACTION99
3.0988-3.90390.18511530.16029254X-RAY DIFFRACTION99
3.9039-45.10.16871590.15539679X-RAY DIFFRACTION100
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)
11.5739-0.21090.22271.3321-0.23251.4607-0.075-0.23650.1110.07990.01690.0961-0.1184-0.19410.03980.11440.0279-0.00570.0979-0.0120.10811.38640.3917-35.9892
21.0544-0.15790.30991.0637-0.41512.0691-0.1388-0.02840.2156-0.02360.0160.0947-0.3065-0.25760.07120.10180.0129-0.0250.07680.00410.14525.2473.5081-47.6645
31.8637-0.2436-0.28861.2085-0.2011.64260.02130.1387-0.1112-0.1177-0.04110.08610.1529-0.13780.02490.105-0.0229-0.0320.07550.00470.10391.6139-8.4653-54.1054
41.53710.32220.59831.554-0.160.33550.02180.1267-0.2357-0.1522-0.028-0.05440.38590.17590.04130.14580.03320.00460.0960.00720.16421.4869-18.5126-45.4158
51.03450.08180.19390.34170.03120.89560.0459-0.0672-0.14650.0263-0.0393-0.0080.2210.03830.01650.1296-0.0054-0.010.0650.02940.128716.8319-15.0843-42.1959
62.1068-0.29290.13720.39230.16263.56230.0386-0.11160.04950.1471-0.0704-0.0364-0.14230.18250.0240.0949-0.0163-0.00640.10550.00830.145624.3679-8.8782-35.365
71.08720.44250.50130.49420.79051.3473-0.10610.09170.40290.0044-0.2319-0.1278-0.50240.12860.08470.255-0.0245-0.03570.24470.15370.2555.202716.4651-86.3451
80.49050.03140.09580.5361-0.44951.1848-0.07440.40840.1694-0.058-0.1877-0.2981-0.12620.69540.04630.152-0.01720.03640.48340.25850.225116.248.658-88.0046
92.39960.43870.18560.5140.62961.23160.08180.1272-0.17070.1109-0.1412-0.16610.28410.39680.02320.18320.0747-0.00570.26860.11820.166914.0462-3.6634-76.4759
101.863-0.2766-0.22451.5514-0.17542.71440.0299-0.0628-0.3133-0.02990.00940.07630.7445-0.2377-0.02880.2626-0.0533-0.01180.22260.0230.1687-6.0207-10.0338-88.2075
111.05840.1810.58360.6467-0.5712.0940.08340.1385-0.1663-0.1617-0.053-0.05010.4509-0.0187-0.03650.2020.04130.01540.18990.02790.1413-1.3062-5.7223-90.0811
121.77340.5128-0.4120.7862-1.37435.4936-0.02370.01590.0223-0.06820.01880.0435-0.1171-0.44490.01760.09310.03370.00030.20890.03690.1532-8.73442.4737-94.3989
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 162 through 285 )
2X-RAY DIFFRACTION2chain 'A' and (resid 286 through 318 )
3X-RAY DIFFRACTION3chain 'A' and (resid 319 through 382 )
4X-RAY DIFFRACTION4chain 'A' and (resid 383 through 452 )
5X-RAY DIFFRACTION5chain 'A' and (resid 453 through 548 )
6X-RAY DIFFRACTION6chain 'A' and (resid 549 through 607 )
7X-RAY DIFFRACTION7chain 'B' and (resid 162 through 202 )
8X-RAY DIFFRACTION8chain 'B' and (resid 203 through 318 )
9X-RAY DIFFRACTION9chain 'B' and (resid 319 through 382 )
10X-RAY DIFFRACTION10chain 'B' and (resid 383 through 452 )
11X-RAY DIFFRACTION11chain 'B' and (resid 453 through 548 )
12X-RAY DIFFRACTION12chain 'B' and (resid 549 through 607 )

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