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- PDB-7q8z: Crystal structure of TTBK2 in complex with VNG1.33 (compound 27) -

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Basic information

Entry
Database: PDB / ID: 7q8z
TitleCrystal structure of TTBK2 in complex with VNG1.33 (compound 27)
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 / kinesin binding / cilium assembly / 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 / cytoplasm / cytosol
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-9IK / PHOSPHATE ION / Tau-tubulin kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.57 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)69,9208
Polymers68,9352
Non-polymers9856
Water13,079726
1
A: Tau-tubulin kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9604
Polymers34,4681
Non-polymers4923
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tau-tubulin kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9604
Polymers34,4681
Non-polymers4923
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.905, 114.745, 120.576
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-9IK / ~{N}-(4-phenoxyphenyl)-7~{H}-pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 302.330 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H14N4O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 726 / 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: 2.81 Å3/Da / Density % sol: 56.15 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 1.6M Na/K phosphate pH 7, 5% Glycerol, 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 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: 1.57→46.39 Å / Num. obs: 106725 / % possible obs: 98.2 % / Redundancy: 10.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.029 / Rrim(I) all: 0.092 / Net I/σ(I): 15.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.57-1.6111.10.892.477210.7880.2920.98697.4
7.02-46.399.50.04513780.9990.0150.04899.7

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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: 1.57→41.56 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.956 / SU B: 2.831 / SU ML: 0.051 / SU R Cruickshank DPI: 0.0752 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.075 / ESU R Free: 0.077 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2033 5204 4.9 %RANDOM
Rwork0.1749 ---
obs0.1763 101443 97.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 92.12 Å2 / Biso mean: 22.032 Å2 / Biso min: 11.1 Å2
Baniso -1Baniso -2Baniso -3
1-0.5 Å20 Å20 Å2
2---0.23 Å20 Å2
3----0.27 Å2
Refinement stepCycle: final / Resolution: 1.57→41.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4765 0 66 726 5557
Biso mean--25.69 33.53 -
Num. residues----587
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0135043
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174862
X-RAY DIFFRACTIONr_angle_refined_deg1.5661.646818
X-RAY DIFFRACTIONr_angle_other_deg1.4361.59311170
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2055623
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.93820.169296
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.2315928
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.7711554
X-RAY DIFFRACTIONr_chiral_restr0.0990.2620
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.025933
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021287
Refine LS restraints NCS

Ens-ID: 1 / Number: 9415 / 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: 1.57→1.611 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.305 379 -
Rwork0.281 7329 -
all-7708 -
obs--97.24 %
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)
10.82370.1926-0.68370.7512-0.39671.5572-0.01980.0332-0.0546-0.0353-0.01530.08390.0571-0.07050.03520.00830.0133-0.00530.0462-0.00820.059225.0421-31.611441.2615
21.9586-2.2396-1.10787.25381.21930.8039-0.14270.1008-0.1081-0.0199-0.04730.2197-0.0142-0.08560.190.1287-0.0071-0.0280.157-0.02920.127727.4224-36.200519.9018
31.21890.1846-0.01441.65160.21591.3194-0.04290.06970.0888-0.14-0.0180.0298-0.11550.02310.06090.04790.0250.01340.05490.03290.059634.0029-19.5823.5064
42.7932-1.27360.06211.651-0.34281.5305-0.0434-0.1738-0.13530.12120.07140.09680.0706-0.1483-0.0280.03410.0050.00010.0486-0.00560.04977.18217.09817.5357
50.9281-0.1219-0.34982.188-0.99391.5308-0.0013-0.0113-0.0420.05240.04540.00710.0031-0.0831-0.04410.00470.0012-0.01380.0218-0.01350.066617.91914.3481-1.6311
61.28710.01630.02391.299-0.15641.8321-0.00420.0543-0.1101-0.05020.02840.01250.1531-0.1014-0.02420.05280.0008-0.02810.0256-0.02120.082518.8216-6.2996-7.3198
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A6 - 171
2X-RAY DIFFRACTION2A172 - 203
3X-RAY DIFFRACTION3A204 - 299
4X-RAY DIFFRACTION4B7 - 99
5X-RAY DIFFRACTION5B100 - 184
6X-RAY DIFFRACTION6B185 - 299

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