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- PDB-7q8v: Crystal structure of TTBK1 in complex with VNG2.73 (compound 42) -

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Basic information

Entry
Database: PDB / ID: 7q8v
TitleCrystal structure of TTBK1 in complex with VNG2.73 (compound 42)
ComponentsTau-tubulin kinase 1
KeywordsTRANSFERASE / kinase / TTBK1 / tau tubulin kinase / kinase inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


positive regulation of astrocyte activation / positive regulation of cyclin-dependent protein kinase activity / positive regulation of microglial cell activation / positive regulation of cysteine-type endopeptidase activity / microtubule associated complex / positive regulation of protein polymerization / tau-protein kinase activity / substantia nigra development / negative regulation of protein binding / peptidyl-threonine phosphorylation ...positive regulation of astrocyte activation / positive regulation of cyclin-dependent protein kinase activity / positive regulation of microglial cell activation / positive regulation of cysteine-type endopeptidase activity / microtubule associated complex / positive regulation of protein polymerization / tau-protein kinase activity / substantia nigra development / negative regulation of protein binding / peptidyl-threonine phosphorylation / tau protein binding / peptidyl-tyrosine phosphorylation / peptidyl-serine phosphorylation / protein tyrosine kinase activity / learning or memory / non-specific serine/threonine protein kinase / protein phosphorylation / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / neuronal cell body / positive regulation of gene expression / perinuclear region of cytoplasm / signal transduction / nucleoplasm / ATP binding / nucleus / cytosol
Similarity search - Function
Tau-tubulin kinase 1, catalytic domain / 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 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.13 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 / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tau-tubulin kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9473
Polymers35,5151
Non-polymers4322
Water1,35175
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)170.915, 39.519, 49.037
Angle α, β, γ (deg.)90.000, 103.080, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Tau-tubulin kinase 1 / Brain-derived tau kinase


Mass: 35515.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTBK1, BDTK, KIAA1855 / Plasmid: pSUMO-LIC / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2
References: UniProt: Q5TCY1, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / 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.: 1 / Source method: obtained synthetically / Formula: C18H13ClN4O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 75 / 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: 2.27 Å3/Da / Density % sol: 45.84 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 29% PEG 3350, 0.2M sodium acetate, 0.1M tris 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00002 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jul 5, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 2.13→47.77 Å / Num. obs: 17584 / % possible obs: 97.1 % / Redundancy: 7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.07 / Rpim(I) all: 0.03 / Rrim(I) all: 0.081 / Net I/σ(I): 13.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.13-2.26.90.903217210.7780.3981.05497.2
8.25-47.776.60.0383410.9980.0160.04298.8

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Processing

Software
NameVersionClassification
Aimless0.7.7data scaling
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7jxx

7jxx


Resolution: 2.13→47.77 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.941 / SU B: 12.648 / SU ML: 0.158 / SU R Cruickshank DPI: 0.2493 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.249 / ESU R Free: 0.207 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2444 899 5.1 %RANDOM
Rwork0.1874 ---
obs0.1903 16685 96.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 131.07 Å2 / Biso mean: 49.496 Å2 / Biso min: 29.09 Å2
Baniso -1Baniso -2Baniso -3
1-1.56 Å2-0 Å2-2.17 Å2
2--2.11 Å20 Å2
3----2.4 Å2
Refinement stepCycle: final / Resolution: 2.13→47.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2380 0 29 75 2484
Biso mean--67.49 49.51 -
Num. residues----292
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0132463
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172370
X-RAY DIFFRACTIONr_angle_refined_deg1.2981.6433310
X-RAY DIFFRACTIONr_angle_other_deg1.2061.5945439
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.145291
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.00920.993141
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.6915457
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.5941522
X-RAY DIFFRACTIONr_chiral_restr0.0610.2295
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.022879
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02613
LS refinement shellResolution: 2.13→2.185 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 76 -
Rwork0.27 1218 -
all-1294 -
obs--96.78 %
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)
13.50210.64490.05824.31630.68082.69990.1252-0.2770.36050.1452-0.03070.309-0.2261-0.2242-0.09460.0549-0.0014-0.00520.1727-0.01790.127271.141439.12439.5007
23.60630.2342-0.61421.613-0.08352.17670.05480.3043-0.1027-0.1564-0.03210.0389-0.0112-0.0213-0.02270.01990.018-0.01790.052-0.04380.051659.228931.0786-12.0024
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A21 - 109
2X-RAY DIFFRACTION2A110 - 312

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