PDB-7qhw: TTBK1 kinase domain in complex with inhibitor 29

ID or keywords:

Entry

Database: PDB / ID: 7qhw

Title

TTBK1 kinase domain in complex with inhibitor 29

Components

Tau-tubulin kinase 1

Keywords

TRANSFERASE / kinase / inhibitor

Function / homology

Function and homology information

positive regulation of astrocyte activation / positive regulation of microglial cell activation / microtubule associated complex / tau-protein kinase activity / positive regulation of protein polymerization / peptidyl-threonine phosphorylation / substantia nigra development / peptidyl-tyrosine phosphorylation / peptidyl-serine phosphorylation / tau protein binding ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.8 Å

Authors

Nozal, V. / Liehta, D.

Funding support

Spain, 2items

Citation

Journal: J.Med.Chem. / Year: 2022
Title: TDP-43 Modulation by Tau-Tubulin Kinase 1 Inhibitors: A New Avenue for Future Amyotrophic Lateral Sclerosis Therapy.
Authors: Nozal, V. / Martinez-Gonzalez, L. / Gomez-Almeria, M. / Gonzalo-Consuegra, C. / Santana, P. / Chaikuad, A. / Perez-Cuevas, E. / Knapp, S. / Lietha, D. / Ramirez, D. / Petralla, S. / Monti, B. ...

History

Deposition	Dec 14, 2021	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Oct 26, 2022	Provider: repository / Type: Initial release
Revision 1.1	Jan 31, 2024	Group: Data collection / Refinement description Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	7qhw.cif.gz	192 KB	Display	PDBx/mmCIF format
PDB format	pdb7qhw.ent.gz		Display	PDB format
PDBx/mmJSON format	7qhw.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	7qhw_validation.pdf.gz	885.5 KB	Display	wwPDB validaton report
Full document	7qhw_full_validation.pdf.gz	893.3 KB	Display
Data in XML	7qhw_validation.xml.gz	23.4 KB	Display
Data in CIF	7qhw_validation.cif.gz	31.6 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/qh/7qhw ftp://data.pdbj.org/pub/pdb/validation_reports/qh/7qhw	HTTPS FTP

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Related structure data

Related structure data	7q8vC 7q8wC 7q8yC 7q8zC 7q90C 4btmS S: Starting model for refinement C: citing same article (ref.)
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

Deposited unit

AAA: Tau-tubulin kinase 1

CCC: Tau-tubulin kinase 1

hetero molecules

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

1

AAA: Tau-tubulin kinase 1

hetero molecules

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

2

CCC: Tau-tubulin kinase 1

hetero molecules

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

Unit cell

Length a, b, c (Å)	126.120, 108.463, 110.314
Angle α, β, γ (deg.)	90.000, 94.512, 90.000
Int Tables number	5
Space group name H-M	C121

#1: Protein	Tau-tubulin kinase 1 / Brain-derived tau kinase Mass: 33965.352 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TTBK1, BDTK, KIAA1855 / Production host: Escherichia coli BL21(DE3) (bacteria) References: UniProt: Q5TCY1, non-specific serine/threonine protein kinase
#2: Chemical	ChemComp-CGI / ~{N}-[4-(4-chloranylphenoxy)phenyl]-7~{H}-pyrrolo[2,3-d]pyrimidin-4-amine Mass: 336.775 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₈H₁₃ClN₄O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	ChemComp-SO4 / SULFATE ION Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO₄
#4: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C₃H₈O₃
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 73 / 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: 5.54 Å³/Da / Density % sol: 77.78 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6 Details: 27% PEG 4000, 200mM NH4SO4, 100 mM Na Citrate pH5.6 and 10 mM TCEP

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.979 Å
Detector	Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 21, 2021
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.979 Å / Relative weight: 1
Reflection	Resolution: 2.8→48.69 Å / Num. obs: 36393 / % possible obs: 99.5 % / Redundancy: 3.4 % / CC_1/2: 0.992 / Net I/σ(I): 5
Reflection shell	Resolution: 2.8→2.873 Å / Num. unique obs: 2552 / CC_1/2: 0.441 / % possible all: 99.78

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0267	refinement
XDS		data reduction
Aimless		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 4BTM

4btm

Resolution: 2.8→48.686 Å / Cor.coef. F_o:F_c: 0.947 / Cor.coef. F_o:F_c free: 0.932 / SU B: 14.942 / SU ML: 0.216 / Cross valid method: FREE R-VALUE / ESU R: 0.329 / ESU R Free: 0.246
Details: Hydrogens have been used if present in the input file

	R_factor	Num. reflection	% reflection
R_free	0.2285	1887	5.185 %
R_work	0.2	34506	-
all	0.201	-	-
obs	-	36393	99.47 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 68.455 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.068 Å²	-0 Å²	0.155 Å²
2-	-	0.196 Å²	0 Å²
3-	-	-	-0.151 Å²

Refinement step

Cycle: LAST / Resolution: 2.8→48.686 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	4765	0	86	73	4924

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.003	0.012	4954
X-RAY DIFFRACTION	r_bond_other_d	0.006	0.02	24
X-RAY DIFFRACTION	r_angle_refined_deg	0.988	1.64	6654
X-RAY DIFFRACTION	r_angle_other_deg	0.283	1.781	48
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	6.522	5	583
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	33.419	20.993	282
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	18.011	15	914
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	15.958	15	44
X-RAY DIFFRACTION	r_chiral_restr	0.086	0.2	591
X-RAY DIFFRACTION	r_gen_planes_refined	0.003	0.02	3722
X-RAY DIFFRACTION	r_nbd_refined	0.215	0.2	2195
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.17	0.2	18
X-RAY DIFFRACTION	r_nbtor_refined	0.312	0.2	3327
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.111	0.2	10
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.161	0.2	151
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.224	0.2	68
X-RAY DIFFRACTION	r_nbd_other	0.219	0.2	2
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.228	0.2	12
X-RAY DIFFRACTION	r_mcbond_it	2.267	5.669	2338
X-RAY DIFFRACTION	r_mcangle_it	3.915	8.501	2919
X-RAY DIFFRACTION	r_scbond_it	2.788	5.981	2616
X-RAY DIFFRACTION	r_scbond_other	2.787	5.982	2617
X-RAY DIFFRACTION	r_scangle_it	4.712	8.829	3735
X-RAY DIFFRACTION	r_scangle_other	4.711	8.83	3736
X-RAY DIFFRACTION	r_lrange_it	8.833	74.074	7341
X-RAY DIFFRACTION	r_lrange_other	8.832	74.081	7342

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 (%)
2.8-2.873	0.396	146	0.369	2552	X-RAY DIFFRACTION	99.7781
2.873-2.951	0.392	126	0.343	2479	X-RAY DIFFRACTION	99.8084
2.951-3.037	0.331	120	0.327	2421	X-RAY DIFFRACTION	99.8036
3.037-3.13	0.318	144	0.315	2322	X-RAY DIFFRACTION	99.7169
3.13-3.233	0.366	121	0.282	2295	X-RAY DIFFRACTION	99.67
3.233-3.346	0.277	126	0.263	2198	X-RAY DIFFRACTION	99.6569
3.346-3.472	0.262	134	0.23	2081	X-RAY DIFFRACTION	98.8839
3.472-3.614	0.263	108	0.208	2052	X-RAY DIFFRACTION	99.8152
3.614-3.775	0.231	96	0.207	1952	X-RAY DIFFRACTION	99.1288
3.775-3.959	0.204	98	0.186	1873	X-RAY DIFFRACTION	98.5993
3.959-4.172	0.202	89	0.169	1782	X-RAY DIFFRACTION	99.8399
4.172-4.425	0.152	86	0.141	1686	X-RAY DIFFRACTION	99.4388
4.425-4.73	0.17	100	0.139	1584	X-RAY DIFFRACTION	99.645
4.73-5.108	0.178	69	0.158	1479	X-RAY DIFFRACTION	99.2944
5.108-5.595	0.205	72	0.159	1375	X-RAY DIFFRACTION	99.7931
5.595-6.253	0.249	71	0.182	1228	X-RAY DIFFRACTION	99.5402
6.253-7.216	0.229	61	0.185	1092	X-RAY DIFFRACTION	99.5682
7.216-8.829	0.151	59	0.156	916	X-RAY DIFFRACTION	98.3855
8.829-12.446	0.135	34	0.136	728	X-RAY DIFFRACTION	98.8327
12.446-48.686	0.292	27	0.222	411	X-RAY DIFFRACTION	97.5501

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	1.3824	1.5879	0.257	4.5421	1.4918	2.0724	0.2119	-0.1674	-0.0099	0.1812	-0.377	0.1562	0.0569	-0.3576	0.1651	0.0966	-0.1067	-0.0419	0.1767	0.0073	0.0992	39.0802	36.0273	5.4499
2	2.2964	1.3443	-0.0511	2.2126	-0.2194	2.2372	-0.3688	0.2381	0.1433	-0.1651	0.3322	0.0925	-0.2607	0.0073	0.0366	0.1737	-0.1217	-0.0812	0.1431	0.0617	0.1364	22.7786	25.8487	-11.0427
3	2.6731	0.3847	0.3849	0.494	-0.4536	1.8106	-0.1292	0.0024	-0.0434	-0.057	0.269	-0.0651	-0.0539	-0.0851	-0.1399	0.3394	-0.0137	-0.0526	0.1982	-0.0692	0.2431	1.6774	-0.8025	-22.8615
4	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0.0579	0	0	0.0579	0	0.0579	0	0	0

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	ALL	AAA	45 - 135
2	X-RAY DIFFRACTION	2	ALL	AAA	136 - 337
3	X-RAY DIFFRACTION	3	ALL	BBB	45 - 76
4	X-RAY DIFFRACTION	4	ALL	BBB	-10000

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