PDB-8uzz: Structure of TDP1 catalytic domain complexed with compound IB03

ID or keywords:

Entry

Database: PDB / ID: 8uzz

Title

Structure of TDP1 catalytic domain complexed with compound IB03

Components

Tyrosyl-DNA phosphodiesterase 1

Keywords

DNA 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 ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.93 Å

Authors

Lountos, 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

Citation

Journal: To Be Published
Title: Structureal analysis of TDP1 in complex with inhbitors
Authors: Lountos, G.T. / Zhao, X.Z. / Barakat, I. / Wang, W. / Agama, K. / Al Mahmud, M.R. / Pommier, Y. / Burke Jr., T.R.

History

Deposition	Nov 16, 2023	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Sep 25, 2024	Provider: repository / Type: Initial release
Revision 1.1	Nov 13, 2024	Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	8uzz.cif.gz	390.3 KB	Display	PDBx/mmCIF format
PDB format	pdb8uzz.ent.gz	316.6 KB	Display	PDB format
PDBx/mmJSON format	8uzz.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	8uzz_validation.pdf.gz	1.2 MB	Display	wwPDB validaton report
Full document	8uzz_full_validation.pdf.gz	1.2 MB	Display
Data in XML	8uzz_validation.xml.gz	46.6 KB	Display
Data in CIF	8uzz_validation.cif.gz	64.6 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/uz/8uzz ftp://data.pdbj.org/pub/pdb/validation_reports/uz/8uzz	HTTPS FTP

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Related structure data

Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#234 - Jun 2019 MDM2 and Cancer similarity (1) #55 - Jul 2004 DNA Ligase similarity (1) #241 - Jan 2020 Twenty Years of Molecules similarity (1)

Deposited unit

A: Tyrosyl-DNA phosphodiesterase 1

B: Tyrosyl-DNA phosphodiesterase 1

hetero molecules

106 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Tyrosyl-DNA phosphodiesterase 1

hetero molecules

defined by author
53 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

2

B: Tyrosyl-DNA phosphodiesterase 1

hetero molecules

defined by author
52.8 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

Unit cell

Length a, b, c (Å)	49.900, 104.992, 193.486
Angle α, β, γ (deg.)	90.00, 90.00, 90.00
Int Tables number	19
Space group name H-M	P2₁2₁2₁

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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

#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, 646 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-YA5 / (8M)-8-{2-[(fluorosulfonyl)oxy]phenyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Mass: 363.317 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₆H₁₀FNO₆S / 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.: 2 / Source method: obtained synthetically / Formula: C₂H₆OS / Comment: DMSO, precipitant*YM
#6: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 632 / Source method: isolated from a natural source / Formula: H₂O

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Details

Has ligand of interest	Y
Has protein modification	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.43 Å³/Da / Density % sol: 49.4 %
Crystal grow	Temperature: 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

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
Detector	Type: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Dec 16, 2021
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1 Å / Relative weight: 1
Reflection	Resolution: 1.93→50 Å / Num. obs: 77695 / % possible obs: 100 % / Redundancy: 7.4 % / CC_1/2: 0.993 / CC star: 0.998 / R_pim(I) all: 0.049 / R_sym value: 0.124 / Net I/σ(I): 16.6
Reflection shell	Resolution: 1.93→1.96 Å / Redundancy: 7 % / Num. unique obs: 3778 / CC_1/2: 0.777 / CC star: 0.935 / R_pim(I) all: 0.395 / R_sym value: 0.968 / % possible all: 100

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Processing

Software

Name	Version	Classification
PHENIX	1.16_3549	refinement
HKL-3000		data reduction
HKL-3000		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.93→40.853 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.76 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.2035	3794	4.89 %
R_work	0.1617	-	-
obs	0.1637	77608	99.79 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL

Refinement step

Cycle: LAST / Resolution: 1.93→40.853 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	7049	0	102	632	7783

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.007	7645
X-RAY DIFFRACTION	f_angle_d	0.868	10420
X-RAY DIFFRACTION	f_dihedral_angle_d	5.445	6915
X-RAY DIFFRACTION	f_chiral_restr	0.057	1077
X-RAY DIFFRACTION	f_plane_restr	0.006	1329

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
1.93-1.9519	0.2614	136	0.2165	2505	X-RAY DIFFRACTION	94
1.9519-1.9776	0.2474	157	0.1996	2715	X-RAY DIFFRACTION	100
1.9776-2.0047	0.2368	128	0.1963	2736	X-RAY DIFFRACTION	100
2.0047-2.0333	0.2225	119	0.1784	2687	X-RAY DIFFRACTION	100
2.0333-2.0637	0.2119	141	0.1836	2710	X-RAY DIFFRACTION	100
2.0637-2.0959	0.2633	136	0.1694	2705	X-RAY DIFFRACTION	100
2.0959-2.1303	0.2364	128	0.1729	2707	X-RAY DIFFRACTION	100
2.1303-2.167	0.2047	154	0.1696	2706	X-RAY DIFFRACTION	100
2.167-2.2064	0.2232	130	0.1644	2695	X-RAY DIFFRACTION	100
2.2064-2.2489	0.2103	143	0.1676	2722	X-RAY DIFFRACTION	100
2.2489-2.2948	0.2138	153	0.1668	2707	X-RAY DIFFRACTION	100
2.2948-2.3447	0.1914	144	0.1615	2701	X-RAY DIFFRACTION	100
2.3447-2.3992	0.2055	113	0.1613	2764	X-RAY DIFFRACTION	100
2.3992-2.4592	0.1964	147	0.1648	2685	X-RAY DIFFRACTION	100
2.4592-2.5257	0.2113	136	0.1619	2717	X-RAY DIFFRACTION	100
2.5257-2.6	0.1984	133	0.1668	2753	X-RAY DIFFRACTION	100
2.6-2.6839	0.2614	155	0.1627	2718	X-RAY DIFFRACTION	100
2.6839-2.7798	0.2444	139	0.1682	2749	X-RAY DIFFRACTION	100
2.7798-2.8911	0.2287	137	0.1702	2728	X-RAY DIFFRACTION	100
2.8911-3.0226	0.2085	143	0.1711	2735	X-RAY DIFFRACTION	100
3.0226-3.1819	0.2126	154	0.1662	2738	X-RAY DIFFRACTION	100
3.1819-3.3812	0.1955	136	0.1676	2760	X-RAY DIFFRACTION	100
3.3812-3.6421	0.1996	137	0.1582	2778	X-RAY DIFFRACTION	100
3.6421-4.0083	0.1712	147	0.1419	2774	X-RAY DIFFRACTION	100
4.0083-4.5876	0.1887	149	0.128	2807	X-RAY DIFFRACTION	100
4.5876-5.7773	0.1533	144	0.1433	2826	X-RAY DIFFRACTION	100
5.7773-40.8	0.1942	155	0.1769	2986	X-RAY DIFFRACTION	100

Refinement TLS params.

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

ID	L11 (°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)
1	1.8786	-0.2198	0.2709	1.3648	-0.2607	1.7252	-0.0668	-0.2755	0.1397	0.0722	0.0031	0.113	-0.1316	-0.2289	0.0529	0.1361	0.0368	-0.0102	0.1361	-0.0153	0.1423	1.4679	0.3695	-35.9147
2	0.9117	0.0573	0.3046	0.8456	0.0452	3.1104	-0.1179	-0.0282	0.1621	-0.0581	0.0207	0.1645	-0.2888	-0.2749	0.0427	0.098	0.01	-0.0168	0.0933	0.0006	0.1775	5.4008	2.4148	-46.1379
3	2.028	-0.3935	-0.3616	0.9557	-0.1406	2.0726	0.0145	0.1302	-0.1558	-0.0942	-0.0093	0.1402	0.1385	-0.1779	-0.0076	0.1239	-0.0277	-0.0367	0.0981	0.0057	0.1519	1.4491	-8.4446	-54.0045
4	3.0135	1.1513	-0.1186	4.3181	-1.3789	1.8822	-0.0743	0.3233	-0.3823	-0.3543	-0.0346	-0.2831	0.5858	0.2016	0.127	0.2221	0.0556	0.0013	0.1609	-0.0261	0.2322	20.9477	-20.046	-51.5749
5	0.9745	0.0117	0.2935	0.1108	0.0341	1.2072	0.0411	-0.0847	-0.1482	0.0167	-0.0128	0.0058	0.233	0.0457	-0.0114	0.1532	0.0028	-0.0108	0.0857	0.0259	0.1648	17.8928	-15.0403	-40.2093
6	2.2781	-0.284	-2.4951	2.1562	-1.8101	7.5654	0.0823	-0.2266	0.6354	0.3853	0.0148	0.0093	-1.6298	1.2772	-0.0082	0.3954	-0.1124	0.0015	0.3924	0.0714	0.399	26.821	3.1524	-49.5902
7	1.5081	-0.1508	0.1607	1.942	-0.0358	2.8852	0.0076	-0.3438	-0.1462	0.114	0.0104	-0.0477	0.3852	0.1131	-0.0058	0.1255	0.002	-0.0144	0.2034	0.0601	0.1816	23.167	-14.5432	-28.8379
8	1.6625	0.3023	0.3577	0.9414	-0.5009	2.2575	-0.0218	0.407	0.2423	-0.0603	-0.2379	-0.2364	-0.2428	0.5509	0.0903	0.1997	-0.037	0.0106	0.3755	0.1785	0.2584	13.6767	11.1892	-89.9136
9	1.2058	-0.0415	0.8642	0.5564	-0.1922	3.0624	0.0577	0.0601	-0.1496	-0.0282	-0.0582	-0.0564	0.4159	0.0207	0.0068	0.1916	0.0303	0.0344	0.1782	0.0522	0.1959	2.9443	-4.1707	-84.2395
10	1.5864	0.3798	-0.2889	0.5657	-1.4405	6.7686	-0.0151	0.073	0.0112	-0.0141	0.0113	0.0277	-0.2327	-0.4781	0.0264	0.1245	0.0231	-0.0003	0.251	0.0235	0.1991	-8.4882	2.6283	-95.0411

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 162 through 280 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 281 through 318 )
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 319 through 382 )
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 383 through 436 )
5	X-RAY DIFFRACTION	5	chain 'A' and (resid 437 through 548 )
6	X-RAY DIFFRACTION	6	chain 'A' and (resid 549 through 568 )
7	X-RAY DIFFRACTION	7	chain 'A' and (resid 569 through 607 )
8	X-RAY DIFFRACTION	8	chain 'B' and (resid 162 through 285 )
9	X-RAY DIFFRACTION	9	chain 'B' and (resid 286 through 548 )
10	X-RAY DIFFRACTION	10	chain 'B' and (resid 549 through 608 )

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