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- PDB-4d2s: Human TTK in complex with a Dyrk1B inhibitor -

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Basic information

Entry
Database: PDB / ID: 4d2s
TitleHuman TTK in complex with a Dyrk1B inhibitor
ComponentsDUAL SPECIFICITY PROTEIN KINASE TTK
KeywordsTRANSFERASE / ONCOLOGY
Function / homology
Function and homology information


protein localization to meiotic spindle midzone / meiotic spindle assembly checkpoint signaling / kinetochore binding / female meiosis chromosome segregation / protein localization to kinetochore / dual-specificity kinase / spindle organization / mitotic spindle assembly checkpoint signaling / protein serine/threonine/tyrosine kinase activity / mitotic spindle organization ...protein localization to meiotic spindle midzone / meiotic spindle assembly checkpoint signaling / kinetochore binding / female meiosis chromosome segregation / protein localization to kinetochore / dual-specificity kinase / spindle organization / mitotic spindle assembly checkpoint signaling / protein serine/threonine/tyrosine kinase activity / mitotic spindle organization / chromosome segregation / spindle / kinetochore / protein tyrosine kinase activity / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / positive regulation of cell population proliferation / ATP binding / membrane / identical protein binding / nucleus / cytoplasm
Similarity search - Function
Protein kinase Mps1 family / Tetratricopeptide-like helical domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Protein kinase Mps1 family / Tetratricopeptide-like helical domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-DYK / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsDebreczeni, J.E. / Kettle, J.G. / Ballard, P. / Bardelle, C. / Butterworth, S. / Colclough, N. / Critchlow, S.E. / Fairley, G. / Fillery, S. / Graham, M.A. ...Debreczeni, J.E. / Kettle, J.G. / Ballard, P. / Bardelle, C. / Butterworth, S. / Colclough, N. / Critchlow, S.E. / Fairley, G. / Fillery, S. / Graham, M.A. / Goodwin, L. / Guichard, S. / Hudson, K. / Mahmood, A. / Vincent, J. / Ward, R.A. / Whittaker, D.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors to Explore a Mek Resistance Hypothesis.
Authors: Kettle, J.G. / Ballard, P. / Bardelle, C. / Cockerill, M. / Colclough, N. / Critchlow, S.E. / Debreczeni, J.E. / Fairley, G. / Fillery, S. / Graham, M.A. / Goodwin, L. / Guichard, S. / ...Authors: Kettle, J.G. / Ballard, P. / Bardelle, C. / Cockerill, M. / Colclough, N. / Critchlow, S.E. / Debreczeni, J.E. / Fairley, G. / Fillery, S. / Graham, M.A. / Goodwin, L. / Guichard, S. / Hudson, K. / Ward, R.A. / Whittaker, D.
History
DepositionMay 12, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 22, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2019Group: Data collection / Experimental preparation ...Data collection / Experimental preparation / Other / Structure summary
Category: audit_author / exptl_crystal_grow / pdbx_database_status
Item: _audit_author.name / _exptl_crystal_grow.method / _pdbx_database_status.status_code_sf

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: DUAL SPECIFICITY PROTEIN KINASE TTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0892
Polymers32,6591
Non-polymers4311
Water362
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)108.013, 113.352, 71.038
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein DUAL SPECIFICITY PROTEIN KINASE TTK / PHOSPHOTYROSINE PICKED THREONINE-PROTEIN KINASE / PYT


Mass: 32658.504 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 512-795
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P33981, dual-specificity kinase
#2: Chemical ChemComp-DYK / N-{2-methoxy-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-4-(1H-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-amine


Mass: 430.502 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26N6O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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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: 3.33 Å3/Da / Density % sol: 63.05 % / Description: NONE
Crystal growMethod: vapor diffusion / Details: 18% PEG3350, 5% ETHANOL, 0.1M NA CITRATE PH 6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.873
DetectorType: MARRESEARCH / Detector: CCD / Date: Apr 13, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873 Å / Relative weight: 1
ReflectionResolution: 2.5→27 Å / Num. obs: 13748 / % possible obs: 88.9 % / Observed criterion σ(I): 2 / Redundancy: 4.2 % / Biso Wilson estimate: 26.1 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 18.61
Reflection shellResolution: 2.5→2.6 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 4.2 / % possible all: 68

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→18.58 Å / Cor.coef. Fo:Fc: 0.9398 / Cor.coef. Fo:Fc free: 0.903 / SU R Cruickshank DPI: 0.206 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.228 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.172
RfactorNum. reflection% reflectionSelection details
Rfree0.221 984 5.11 %RANDOM
Rwork0.179 ---
obs0.1811 13748 95.59 %-
Displacement parametersBiso mean: 28.35 Å2
Baniso -1Baniso -2Baniso -3
1-1.829 Å20 Å20 Å2
2---1.9539 Å20 Å2
3---0.1249 Å2
Refine analyzeLuzzati coordinate error obs: 0.238 Å
Refinement stepCycle: LAST / Resolution: 2.5→18.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1903 0 32 2 1937
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012436HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.033301HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d844SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes59HARMONIC2
X-RAY DIFFRACTIONt_gen_planes351HARMONIC5
X-RAY DIFFRACTIONt_it2436HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.44
X-RAY DIFFRACTIONt_other_torsion15.96
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion304SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3078SEMIHARMONIC4
LS refinement shellResolution: 2.1→2.21 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2141 125 4.94 %
Rwork0.1812 2405 -
all0.1827 2530 -
obs--95.59 %
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)
12.3045-0.1003-0.37711.0987-0.35691.6214-0.0538-0.2134-0.27570.2296-0.0557-0.10530.4450.23220.10960.16450.04060.00650.00350.0789-0.009521.8758-4.856460.8002
21.981-0.12930.31720.884-0.10930.995-0.00850.2393-0.05830.0068-0.00980.0921-0.02120.00020.0183-0.04720.00270.0114-0.03-0.0077-0.069214.36019.077339.5309
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|985 - A|1082 }
2X-RAY DIFFRACTION2{ A|1083 - A|1286 }

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