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- PDB-7jxx: Structure of TTBK1 kinase domain in complex with Compound 3 -

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Basic information

Entry
Database: PDB / ID: 7jxx
TitleStructure of TTBK1 kinase domain in complex with Compound 3
ComponentsTau-tubulin kinase 1
KeywordsTRANSFERASE/INHIBITOR / tau tubulin binding kinase / kinase / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


positive regulation of cyclin-dependent protein kinase activity / positive regulation of astrocyte activation / 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 cyclin-dependent protein kinase activity / positive regulation of astrocyte activation / 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-VP7 / Tau-tubulin kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.56 Å
AuthorsChodaprambil, J.V.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo.
Authors: Halkina, T. / Henderson, J.L. / Lin, E.Y. / Himmelbauer, M.K. / Jones, J.H. / Nevalainen, M. / Feng, J. / King, K. / Rooney, M. / Johnson, J.L. / Marcotte, D.J. / Chodaparambil, J.V. / ...Authors: Halkina, T. / Henderson, J.L. / Lin, E.Y. / Himmelbauer, M.K. / Jones, J.H. / Nevalainen, M. / Feng, J. / King, K. / Rooney, M. / Johnson, J.L. / Marcotte, D.J. / Chodaparambil, J.V. / Kumar, P.R. / Patterson, T.A. / Murugan, P. / Schuman, E. / Wong, L. / Hesson, T. / Lamore, S. / Bao, C. / Calhoun, M. / Certo, H. / Amaral, B. / Dillon, G.M. / Gilfillan, R. / de Turiso, F.G.
History
DepositionAug 28, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 19, 2021Provider: repository / Type: Initial release
Revision 1.1May 26, 2021Group: 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 1.2Oct 18, 2023Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tau-tubulin kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2855
Polymers37,8841
Non-polymers4014
Water5,242291
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)173.837, 34.337, 48.666
Angle α, β, γ (deg.)90.000, 103.498, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

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


Mass: 37883.574 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTBK1, BDTK, KIAA1855 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q5TCY1, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-VP7 / 4-(2-amino-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-11-yl)-2-methylbut-3-yn-2-ol


Mass: 332.399 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 291 / 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: 1.86 Å3/Da / Density % sol: 34.01 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 0.1M TRIS pH 8.5, 0.2M Na Acetate 20% PEG3350

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jul 14, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.56→50 Å / Num. obs: 39721 / % possible obs: 99 % / Redundancy: 3.7 % / Biso Wilson estimate: 21.31 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.04 / Net I/σ(I): 15.4
Reflection shellResolution: 1.56→1.59 Å / Rmerge(I) obs: 1.2 / Num. unique obs: 5534 / CC1/2: 0.5 / Rsym value: 0.9

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874+SVNrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NFM

4nfm


Resolution: 1.56→28.4 Å / SU ML: 0.2044 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 21.8528
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2126 2059 5.21 %
Rwork0.1797 37460 -
obs0.1813 39519 97.43 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 34.64 Å2
Refinement stepCycle: LAST / Resolution: 1.56→28.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2322 0 28 291 2641
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01252551
X-RAY DIFFRACTIONf_angle_d1.32613465
X-RAY DIFFRACTIONf_chiral_restr0.0764367
X-RAY DIFFRACTIONf_plane_restr0.0086449
X-RAY DIFFRACTIONf_dihedral_angle_d17.9424999
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.56-1.590.32481280.30882406X-RAY DIFFRACTION95.41
1.59-1.630.30971400.28942463X-RAY DIFFRACTION96.48
1.63-1.680.32451290.27332451X-RAY DIFFRACTION96.92
1.68-1.730.30041550.24942461X-RAY DIFFRACTION97.61
1.73-1.780.27911420.23872487X-RAY DIFFRACTION97.3
1.78-1.850.27981210.232472X-RAY DIFFRACTION97.52
1.85-1.920.26931510.20862502X-RAY DIFFRACTION97.79
1.92-2.010.21611240.19092515X-RAY DIFFRACTION98.18
2.01-2.110.21281130.1792532X-RAY DIFFRACTION97.85
2.11-2.240.18151230.17442500X-RAY DIFFRACTION98.46
2.24-2.420.22091440.17562524X-RAY DIFFRACTION98.31
2.42-2.660.21321510.17452526X-RAY DIFFRACTION98.49
2.66-3.050.22941680.18052503X-RAY DIFFRACTION98.05
3.05-3.830.16471480.14982568X-RAY DIFFRACTION98.84
3.84-28.40.18391220.15422550X-RAY DIFFRACTION94.35
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)
11.24308960043-1.38786937831.298976813242.33053475298-1.232504823921.540114877520.148205872436-0.675712921715-1.440911661050.277074287170.2617757281271.014260705730.214831786535-0.655091834071-0.1546616213340.24995706741-0.0833092374165-0.002420799305820.2997291927310.1805899150240.564993096192177.8818651045.0564471793966.8954089748
23.670301751750.174147779956-1.26601220971.555014361420.02811136590310.6207569520440.1240587860140.4970196168590.684553847236-0.237315359229-0.0687026694273-0.199404659234-0.4875228115210.802750787392-0.1707406481120.331955105395-0.1663952984720.04014856907530.5841419063440.09649061328630.267341334991174.42956664624.697262431237.0268026642
34.17899263198-0.3166526625991.886218735821.29872622427-0.193236389441.120730707670.1726751822460.777927562669-0.318232163841-0.208277772513-0.000927747482863-0.1128435051790.07419839674760.22181242831-0.08717021972140.1645558481410.007323694087710.0279995926140.246975420791-0.05956252672970.144739741604185.13716363912.652185501451.3881232052
43.21644116895-0.1460718636331.421844915263.80602826720.1882424706432.799999573790.0573157345180.118947989364-0.2278196790410.0615606499790.085675651055-0.160179414876-0.08788766721920.0755959838765-0.1211565115730.1699731857450.0131070608678-0.02831430022410.086446384825-0.009835684172670.212709279345196.93453489412.358489010864.8577159697
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 286 through 312 )286 - 312286 - 313
22chain 'A' and (resid 22 through 73 )22 - 731 - 53
33chain 'A' and (resid 74 through 234 )74 - 23454 - 229
44chain 'A' and (resid 235 through 285 )235 - 285230 - 285

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