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- PDB-7q8y: Crystal structure of TTBK2 in complex with VNG2.73 (compound 42) -

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Basic information

Entry
Database: PDB / ID: 7q8y
TitleCrystal structure of TTBK2 in complex with VNG2.73 (compound 42)
ComponentsTau-tubulin kinase 2
KeywordsTRANSFERASE / kinase / TTBK2 / tau tubulin kinase / kinase inhibitor
Function / homology
Function and homology information


negative regulation of protein localization to microtubule / cerebellar granular layer development / cerebellar granule cell precursor tangential migration / positive regulation of non-motile cilium assembly / protein localization to organelle / ciliary transition zone / negative regulation of microtubule depolymerization / embryonic brain development / microtubule plus-end binding / regulation of smoothened signaling pathway ...negative regulation of protein localization to microtubule / cerebellar granular layer development / cerebellar granule cell precursor tangential migration / positive regulation of non-motile cilium assembly / protein localization to organelle / ciliary transition zone / negative regulation of microtubule depolymerization / embryonic brain development / microtubule plus-end binding / regulation of smoothened signaling pathway / neural tube development / tau-protein kinase activity / embryonic digit morphogenesis / smoothened signaling pathway / ciliary base / forebrain development / cilium assembly / kinesin binding / centriole / Anchoring of the basal body to the plasma membrane / regulation of cell migration / cerebellum development / peptidyl-serine phosphorylation / microtubule cytoskeleton organization / tau protein binding / microtubule cytoskeleton / non-specific serine/threonine protein kinase / cilium / ciliary basal body / protein serine kinase activity / protein serine/threonine kinase activity / signal transduction / extracellular space / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / : / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-9IV / PHOSPHATE ION / Tau-tubulin kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsChaikuad, A. / Nozal, V. / Martinez, A. / Knapp, S. / Structural Genomics Consortium (SGC)
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Innovative Medicines Initiative Switzerland
CitationJournal: 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. ...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. / Gil, C. / Martin-Requero, A. / Palomo, V. / de Lago, E. / Martinez, A.
History
DepositionNov 11, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 9, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tau-tubulin kinase 2
B: Tau-tubulin kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,9898
Polymers68,9352
Non-polymers1,0536
Water13,313739
1
A: Tau-tubulin kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9944
Polymers34,4681
Non-polymers5273
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tau-tubulin kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9944
Polymers34,4681
Non-polymers5273
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.861, 114.745, 120.550
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: GLN / Beg label comp-ID: GLN / End auth comp-ID: GLU / End label comp-ID: GLU / Refine code: _ / Auth seq-ID: 7 - 298 / Label seq-ID: 8 - 299

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein Tau-tubulin kinase 2


Mass: 34467.723 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTBK2, KIAA0847 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2
References: UniProt: Q6IQ55, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-9IV / ~{N}-[4-(2-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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 739 / 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: 2.8 Å3/Da / Density % sol: 56.11 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 1.6M Na/K phosphate pH 7, 5% Glycerol, 0.1M tris 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Apr 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→46.36 Å / Num. obs: 102766 / % possible obs: 99.9 % / Redundancy: 10.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.07 / Rpim(I) all: 0.024 / Rrim(I) all: 0.077 / Net I/σ(I): 18.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.6-1.6410.80.8922.575370.7880.2980.988100
7.16-46.369.60.03613060.9990.0120.03899.7

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6u0k

6u0k


Resolution: 1.6→46.36 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.953 / SU B: 2.982 / SU ML: 0.053 / SU R Cruickshank DPI: 0.0794 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.079 / ESU R Free: 0.08 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2052 5014 4.9 %RANDOM
Rwork0.1777 ---
obs0.179 97667 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 67.16 Å2 / Biso mean: 19.081 Å2 / Biso min: 7.91 Å2
Baniso -1Baniso -2Baniso -3
1-0.15 Å20 Å20 Å2
2---0.01 Å20 Å2
3----0.14 Å2
Refinement stepCycle: final / Resolution: 1.6→46.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4761 0 92 739 5592
Biso mean--29.68 34.72 -
Num. residues----587
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0135033
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174823
X-RAY DIFFRACTIONr_angle_refined_deg1.611.6396798
X-RAY DIFFRACTIONr_angle_other_deg1.4481.59611069
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3865611
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.00220.205293
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.28915914
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8081553
X-RAY DIFFRACTIONr_chiral_restr0.0960.2614
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.026039
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021287
Refine LS restraints NCS

Ens-ID: 1 / Number: 9381 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.12 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.6→1.642 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.291 394 -
Rwork0.266 7133 -
all-7527 -
obs--99.97 %
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)
11.09820.3287-0.67250.818-0.44471.7683-0.01120.0474-0.0802-0.0228-0.02160.07070.0563-0.05730.03280.00610.0051-0.0020.0139-0.00990.018725.4491-31.923140.9774
21.1141-0.0689-0.05822.11060.26671.0646-0.01570.10590.0316-0.1892-0.05520.1316-0.0542-0.04110.07090.04390.0320.00160.04440.01610.022232.1896-22.821822.6168
34.14850.3871-0.61043.9333-1.8423.7734-0.0625-0.1336-0.18550.09420.07560.06860.1292-0.2145-0.01310.02810.0119-0.00110.04290.00050.01262.786919.64366.066
40.7459-0.229-0.20051.46540.29670.96090.00960.0112-0.0641-0.00690.03440.02720.0958-0.0873-0.0440.017-0.0077-0.01750.01680.00280.026617.38960.8196-2.487
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A6 - 176
2X-RAY DIFFRACTION2A177 - 299
3X-RAY DIFFRACTION3B7 - 58
4X-RAY DIFFRACTION4B59 - 299

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