PDB-6tkr: Tankyrase 2 in complex with an inhibitor (OM-1704)

ID or keywords:

Entry

Database: PDB / ID: 6tkr

Title

Tankyrase 2 in complex with an inhibitor (OM-1704)

Components

Tankyrase-2

Keywords

TRANSFERASE / Inhibitor / Complex / Poly-ADP-ribosylation / Enzyme

Function / homology

Function and homology information

XAV939 stabilizes AXIN / positive regulation of telomere capping / NAD+ ADP-ribosyltransferase / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / protein localization to chromosome, telomeric region / NAD+-protein-aspartate ADP-ribosyltransferase activity / protein poly-ADP-ribosylation / NAD+-protein-glutamate ADP-ribosyltransferase activity / NAD+-protein mono-ADP-ribosyltransferase activity ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.75 Å

Authors

Sowa, S.T. / Lehtio, L.

Funding support

Finland, 2items

Citation

Journal: J.Med.Chem. / Year: 2020
Title: Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.
Authors: Waaler, J. / Leenders, R.G.G. / Sowa, S.T. / Alam Brinch, S. / Lycke, M. / Nieczypor, P. / Aertssen, S. / Murthy, S. / Galera-Prat, A. / Damen, E. / Wegert, A. / Nazare, M. / Lehtio, L. / Krauss, S.

History

Deposition	Nov 28, 2019	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Jul 8, 2020	Provider: repository / Type: Initial release
Revision 1.1	Jul 22, 2020	Group: 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 1.2	Jan 24, 2024	Group: Data collection / Database references / Refinement description Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	6tkr.cif.gz	175.6 KB	Display	PDBx/mmCIF format
PDB format	pdb6tkr.ent.gz		Display	PDB format
PDBx/mmJSON format	6tkr.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	6tkr_validation.pdf.gz	824.5 KB	Display	wwPDB validaton report
Full document	6tkr_full_validation.pdf.gz	830.4 KB	Display
Data in XML	6tkr_validation.xml.gz	18.4 KB	Display
Data in CIF	6tkr_validation.cif.gz	23.5 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/tk/6tkr ftp://data.pdbj.org/pub/pdb/validation_reports/tk/6tkr	HTTPS FTP

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Related structure data

Related structure data	6tg4C 6tkmC 6tknC 6tkpC 6tkqC 6tksC 5nobS S: Starting model for refinement C: citing same article (ref.)
Similar structure data	6tkp-2 3uh2-1 4l09-1 6tg4-2 6tkn-1 5aeh-2 4bjb-d 4bjc-d 6tkm-2 5aeh-1 Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) 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	#250 - Oct 2020 Capsaicin Receptor TRPV1 similarity (1) #60 - Dec 2004 Ubiquitin similarity (1) #223 - Jul 2018 Piezo1 Mechanosensitive Channel similarity (1) #234 - Jun 2019 MDM2 and Cancer similarity (1)

Deposited unit

AAA: Tankyrase-2

BBB: Tankyrase-2

hetero molecules

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

1

AAA: Tankyrase-2

hetero molecules

defined by author
Evidence: gel filtration, Based on gel filtration, this runs as a monomer.
27.9 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

2

BBB: Tankyrase-2

hetero molecules

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

Unit cell

Length a, b, c (Å)	41.990, 76.760, 148.120
Angle α, β, γ (deg.)	90.000, 90.000, 90.000
Int Tables number	19
Space group name H-M	P2₁2₁2₁

Noncrystallographic symmetry (NCS)

NCS domain: (Details: Chains A B)

#1: Protein	Tankyrase-2 / TANK2 / ADP-ribosyltransferase diphtheria toxin-like 6 / ARTD6 / Poly [ADP-ribose] polymerase 5B / ...TANK2 / ADP-ribosyltransferase diphtheria toxin-like 6 / ARTD6 / Poly [ADP-ribose] polymerase 5B / TNKS-2 / TRF1-interacting ankyrin-related ADP-ribose polymerase 2 / Tankyrase II / Tankyrase-like protein / Tankyrase-related protein Mass: 27299.764 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS2, PARP5B, TANK2, TNKL / Production host: Escherichia coli (E. coli) References: UniProt: Q9H2K2, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Chemical	ChemComp-NJK / ~{N}-[3-[5-(5-ethoxypyridin-2-yl)-4-(2-fluorophenyl)-1,2,4-triazol-3-yl]cyclobutyl]-1,5-naphthyridine-2-carboxamide Mass: 509.534 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₈H₂₄FN₇O₂ / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 26 / Source method: isolated from a natural source / Formula: H₂O
Has ligand of interest	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: 2.53 Å³/Da / Density % sol: 51.42 %
Crystal grow	Temperature: 295.15 K / Method: vapor diffusion, sitting drop / Details: 7.5-25% PEG6000, Bicine pH=9.0

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
Detector	Type: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jul 1, 2018
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.9795 Å / Relative weight: 1
Reflection	Resolution: 2.75→50 Å / Num. obs: 12895 / % possible obs: 98.7 % / Redundancy: 6.397 % / CC_1/2: 0.99 / Net I/σ(I): 5.66
Reflection shell	Resolution: 2.75→2.82 Å / Num. unique obs: 952 / CC_1/2: 0.685

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0257	refinement
XDS		data reduction
XSCALE		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 5NOB

5nob

Resolution: 2.75→41.56 Å / Cor.coef. F_o:F_c: 0.937 / Cor.coef. F_o:F_c free: 0.923 / SU B: 24.69 / SU ML: 0.435 / Cross valid method: FREE R-VALUE / ESU R Free: 0.406
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2743	645	5.002 %
R_work	0.2208	-	-
all	0.224	-	-
obs	-	12894	98.669 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å

Displacement parameters

B_iso mean: 50.105 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	1.184 Å²	0 Å²	0 Å²
2-	-	4.478 Å²	-0 Å²
3-	-	-	-5.662 Å²

Refinement step

Cycle: LAST / Resolution: 2.75→41.56 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	3284	0	78	26	3388

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.006	0.013	3464
X-RAY DIFFRACTION	r_bond_other_d	0.002	0.018	3019
X-RAY DIFFRACTION	r_angle_refined_deg	1.396	1.68	4674
X-RAY DIFFRACTION	r_angle_other_deg	1.218	1.601	6990
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	7.758	5	409
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	32.748	21.176	204
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	16.482	15	551
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	14.736	15	27
X-RAY DIFFRACTION	r_chiral_restr	0.054	0.2	418
X-RAY DIFFRACTION	r_chiral_restr_other	1.509	0.2	8
X-RAY DIFFRACTION	r_gen_planes_refined	0.005	0.02	3934
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	813
X-RAY DIFFRACTION	r_nbd_refined	0.196	0.2	664
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.182	0.2	2849
X-RAY DIFFRACTION	r_nbtor_refined	0.168	0.2	1596
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.075	0.2	1589
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.154	0.2	90
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.1	0.2	1
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.22	0.2	11
X-RAY DIFFRACTION	r_nbd_other	0.274	0.2	29
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.224	0.2	4
X-RAY DIFFRACTION	r_mcbond_it	3.256	5.354	1645
X-RAY DIFFRACTION	r_mcbond_other	3.255	5.352	1644
X-RAY DIFFRACTION	r_mcangle_it	5.401	8.007	2048
X-RAY DIFFRACTION	r_mcangle_other	5.4	8.009	2049
X-RAY DIFFRACTION	r_scbond_it	3.117	5.528	1819
X-RAY DIFFRACTION	r_scbond_other	3.116	5.527	1820
X-RAY DIFFRACTION	r_scangle_it	5.207	8.172	2621
X-RAY DIFFRACTION	r_scangle_other	5.206	8.171	2622
X-RAY DIFFRACTION	r_lrange_it	8.249	59.276	3764
X-RAY DIFFRACTION	r_lrange_other	8.244	59.268	3763
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.106	0.05	6357

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 (%)
2.75-2.822	0.436	47	0.382	902	X-RAY DIFFRACTION	99.8947
2.822-2.899	0.35	45	0.368	854	X-RAY DIFFRACTION	99.778
2.899-2.983	0.44	46	0.352	867	X-RAY DIFFRACTION	99.8906
2.983-3.075	0.397	43	0.328	821	X-RAY DIFFRACTION	99.8844
3.075-3.176	0.38	42	0.291	791	X-RAY DIFFRACTION	99.8801
3.176-3.287	0.309	41	0.28	786	X-RAY DIFFRACTION	99.6385
3.287-3.411	0.322	39	0.231	739	X-RAY DIFFRACTION	99.8716
3.411-3.55	0.184	39	0.223	741	X-RAY DIFFRACTION	99.872
3.55-3.708	0.346	29	0.213	545	X-RAY DIFFRACTION	78.8462
3.708-3.889	0.247	35	0.198	679	X-RAY DIFFRACTION	99.7207
3.889-4.099	0.226	34	0.177	634	X-RAY DIFFRACTION	100
4.099-4.347	0.248	32	0.174	609	X-RAY DIFFRACTION	99.8442
4.347-4.647	0.259	31	0.162	584	X-RAY DIFFRACTION	100
4.647-5.019	0.225	27	0.151	523	X-RAY DIFFRACTION	99.8185
5.019-5.498	0.174	27	0.163	512	X-RAY DIFFRACTION	100
5.498-6.146	0.273	24	0.205	454	X-RAY DIFFRACTION	100
6.146-7.094	0.215	21	0.182	406	X-RAY DIFFRACTION	100
7.094-8.684	0.215	19	0.166	353	X-RAY DIFFRACTION	100
8.684-12.26	0.214	15	0.162	278	X-RAY DIFFRACTION	100

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