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- PDB-7jxy: Structure of TTBK1 kinase domain in complex with Compound 18 -

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Basic information

Entry
Database: PDB / ID: 7jxy
TitleStructure of TTBK1 kinase domain in complex with Compound 18
ComponentsTau-tubulin kinase 1
KeywordsTRANSFERASE/INHIBITOR / tau tubulin binding kinase / kinase / TRANSFERASE / TRANSFERASE-INHIBITOR complex
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-VSY / Tau-tubulin kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 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
B: Tau-tubulin kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,3844
Polymers75,7672
Non-polymers6172
Water63135
1
A: Tau-tubulin kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1922
Polymers37,8841
Non-polymers3081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tau-tubulin kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1922
Polymers37,8841
Non-polymers3081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)87.280, 87.280, 151.430
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Space group name HallP4nw2abw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+3/4
#3: y+1/2,-x+1/2,z+1/4
#4: x+1/2,-y+1/2,-z+1/4
#5: -x+1/2,y+1/2,-z+3/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

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


Mass: 37883.574 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: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q5TCY1, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-VSY / (3S)-1-[1-(2-aminopyrimidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-methylpent-1-yn-3-ol


Mass: 308.338 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H16N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 35 / 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: 1.9 Å3/Da / Density % sol: 35.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 0.1M BisTRIS pH 6.0 and 35% PEG3350

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.97 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 14, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 36437 / % possible obs: 99 % / Redundancy: 12.7 % / Biso Wilson estimate: 54.48 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.18 / Net I/σ(I): 17.9
Reflection shellResolution: 2.15→2.21 Å / Num. unique obs: 5120 / CC1/2: 0.53

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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: 2.15→47.84 Å / SU ML: 0.2288 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 21.9573
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2411 1634 5.01 %
Rwork0.2004 31000 -
obs0.2024 32634 99.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 64.46 Å2
Refinement stepCycle: LAST / Resolution: 2.15→47.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4564 0 46 35 4645
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00484715
X-RAY DIFFRACTIONf_angle_d0.99086365
X-RAY DIFFRACTIONf_chiral_restr0.0519679
X-RAY DIFFRACTIONf_plane_restr0.0062816
X-RAY DIFFRACTIONf_dihedral_angle_d17.34281749
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.210.24931310.20152484X-RAY DIFFRACTION98.16
2.21-2.280.21181340.19222539X-RAY DIFFRACTION100
2.28-2.360.24311340.2012537X-RAY DIFFRACTION100
2.36-2.460.21251340.20622550X-RAY DIFFRACTION100
2.46-2.570.26561360.22262576X-RAY DIFFRACTION100
2.57-2.710.26611330.23232527X-RAY DIFFRACTION100
2.71-2.880.28031350.23882561X-RAY DIFFRACTION100
2.88-3.10.27741350.23362580X-RAY DIFFRACTION100
3.1-3.410.28631350.22812585X-RAY DIFFRACTION100
3.41-3.90.24061380.20222608X-RAY DIFFRACTION100
3.9-4.920.21681400.17542652X-RAY DIFFRACTION100
4.92-47.840.22331490.18562801X-RAY DIFFRACTION100
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)
12.12425032988-1.177697430941.717693224422.005888065181.165276570485.124183205450.2811285865850.241980854463-0.0961968667329-0.04865851546260.165262977283-0.4824475258040.167601543860.533445840758-0.3503265482730.472165849535-0.00824956245869-0.008035044742170.512668435618-0.1673679820260.58889258447-16.7815498655-33.72932468149.54005026281
23.62480942672-0.4045682900751.367976434092.959474896450.7840659149373.061953743830.08661359882320.1466161670780.195658297926-0.102108127481-0.1466618530490.106552845742-0.274122256962-0.05834082856710.06155500733060.3746140549730.02197738305550.0367206922260.364175496248-0.04440550392740.315450537333-15.6334740879-16.292395983123.7447018626
32.710943157750.6515403796511.862392705991.982281003840.5289922176412.5706539974-0.1651420786710.142853841472-0.141000624143-0.274340447416-0.01615817238520.322650715419-0.192563330753-0.2048534421940.1590556016560.471461866523-0.0354031271774-0.03788126688470.6229529493140.01636064207810.550637043806-28.1613024679-37.529611092539.1343593742
43.34047209634-0.1244348729761.552158211152.40669425937-0.1490620864444.434044478710.150135864444-0.370742562148-0.592350599177-0.00364080417798-0.01695745080070.07802793033141.0918244129-0.785577563833-0.1750101160280.574253383942-0.013131357431-0.08093927699520.5395731927360.1212892410180.775962687167-16.8741153675-52.230744803354.8045195997
53.650443159110.713889468921.79812393432.34571661474-0.0878258300573.72007824054-0.07586841393760.1658878840090.06066960968010.0441899931499-0.02194142137240.253865341669-0.332565956853-0.1412584109080.07458664666890.388017337008-0.05743363276-0.0533962188840.4703994136940.02491370628220.440056873673-15.8294640598-35.987845980553.293231178
62.86549845506-0.1116773679520.7494319202152.69072293535-0.04121740706264.01022380570.00541652773084-0.582225024498-0.05495637879680.747993793767-0.1859902844690.0744440180403-0.0963356928243-0.1462213209810.1234543508690.623321576802-0.084384144849-0.04499167720010.5812306877290.07720857154660.464955490909-14.9058188752-36.36397362368.1336003743
71.71081309918-0.2503278644880.6267194302191.949024900810.6354843480711.376405167270.2436611288190.423137680641-0.241235966607-0.349845375633-0.121886680037-0.335335965190.1091120700480.599412874219-0.1438108098780.6371094145340.0464744550422-0.1200466033120.694851092858-0.01484141536810.579599405108-1.53485762661-44.972340828956.433324671
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 23 through 92 )AA23 - 921 - 70
22chain 'A' and (resid 93 through 312 )AA93 - 31271 - 290
33chain 'B' and (resid 20 through 108 )BC20 - 1081 - 89
44chain 'B' and (resid 109 through 127 )BC109 - 12790 - 108
55chain 'B' and (resid 128 through 204 )BC128 - 204109 - 180
66chain 'B' and (resid 205 through 285 )BC205 - 285181 - 261
77chain 'B' and (resid 286 through 312 )BC286 - 312262 - 288

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