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- PDB-6n6o: Crystal structure of the human TTK in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 6n6o
TitleCrystal structure of the human TTK in complex with an inhibitor
ComponentsDual specificity protein kinase TTK
KeywordsSIGNALING PROTEIN / Protein Kinase Activity Protein Serine/Threonine/Tyrosine kinase activity ATP Binding Protein Phosphorylation Mitotic Cell Cycle Checkpoint Chromosome Separation
Function / homology
Function and homology information


protein localization to meiotic spindle midzone / meiotic spindle assembly checkpoint signaling / repair of mitotic kinetochore microtubule attachment defect / 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 ...protein localization to meiotic spindle midzone / meiotic spindle assembly checkpoint signaling / repair of mitotic kinetochore microtubule attachment defect / 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 / kinetochore / spindle / protein tyrosine kinase activity / protein serine kinase activity / protein serine/threonine kinase activity / positive regulation of cell population proliferation / ATP binding / identical protein binding / membrane / 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-KE7 / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsFenalti, G.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy.
Authors: Riggs, J.R. / Elsner, J. / Cashion, D. / Robinson, D. / Tehrani, L. / Nagy, M. / Fultz, K.E. / Krishna Narla, R. / Peng, X. / Tran, T. / Kulkarni, A. / Bahmanyar, S. / Condroski, K. / ...Authors: Riggs, J.R. / Elsner, J. / Cashion, D. / Robinson, D. / Tehrani, L. / Nagy, M. / Fultz, K.E. / Krishna Narla, R. / Peng, X. / Tran, T. / Kulkarni, A. / Bahmanyar, S. / Condroski, K. / Pagarigan, B. / Fenalti, G. / LeBrun, L. / Leftheris, K. / Zhu, D. / Boylan, J.F.
History
DepositionNov 26, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 15, 2019Provider: repository / Type: Initial release
Revision 1.1May 22, 2019Group: Data collection / 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 30, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)33,7834
Polymers32,9271
Non-polymers8563
Water543
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.410, 71.410, 122.491
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Dual specificity protein kinase TTK / Phosphotyrosine picked threonine-protein kinase / PYT


Mass: 32926.793 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTK, MPS1, MPS1L1 / Production host: Escherichia coli (E. coli) / References: UniProt: P33981, dual-specificity kinase
#2: Chemical ChemComp-KE7 / 4-({5-chloro-4-[(cis-4-hydroxy-4-methylcyclohexyl)oxy]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)-N,N-dimethyl-3-{[(2R)-1,1,1-trifluoropropan-2-yl]oxy}benzamide


Mass: 555.977 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H29ClF3N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.9 Å3/Da / Density % sol: 57.67 % / Description: Prisms
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 100mM Tris pH 8.5, 300mM Sodium Acetate, 8% PEG 20k, 8% PEG 500 MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9794 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: May 2, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9794 Å / Relative weight: 1
ReflectionResolution: 2.6→61.843 Å / Num. all: 11650 / Num. obs: 11650 / % possible obs: 100 % / Redundancy: 7.2 % / Rpim(I) all: 0.027 / Rrim(I) all: 0.072 / Rsym value: 0.067 / Net I/av σ(I): 8 / Net I/σ(I): 16.8 / Num. measured all: 84416
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
2.6-2.747.40.5571.416830.2180.60.557100
2.74-2.917.40.3272.415590.1280.3520.327100
2.91-3.117.40.2063.714950.0810.2220.206100
3.11-3.367.30.1295.513820.0510.1390.129100
3.36-3.687.30.0887.312780.0340.0940.088100
3.68-4.117.30.04713.911740.0180.0510.047100
4.11-4.757.20.05410.810480.0210.0580.054100
4.75-5.817.10.0589.68880.0240.0630.058100
5.81-8.226.90.04214.97160.0160.0450.042100
8.22-61.2456.30.0319.14270.0130.0330.0399.2

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Processing

Software
NameVersionClassification
MOSFLM7.2.1data reduction
SCALA3.3.22data scaling
REFMAC5.8.0135refinement
PDB_EXTRACT3.24data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→61.84 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.919 / SU B: 10.423 / SU ML: 0.223 / SU R Cruickshank DPI: 0.4279 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.428 / ESU R Free: 0.274
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2439 518 4.5 %RANDOM
Rwork0.1999 ---
obs0.2021 11099 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 124.02 Å2 / Biso mean: 56.113 Å2 / Biso min: 35.31 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å20.29 Å20 Å2
2--0.57 Å20 Å2
3----1.85 Å2
Refinement stepCycle: final / Resolution: 2.6→61.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1949 0 58 3 2010
Biso mean--55.89 48.48 -
Num. residues----254
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192051
X-RAY DIFFRACTIONr_bond_other_d0.0020.021907
X-RAY DIFFRACTIONr_angle_refined_deg1.7461.9572786
X-RAY DIFFRACTIONr_angle_other_deg1.0312.9914342
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3875251
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.72824.87580
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.51815326
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.804155
X-RAY DIFFRACTIONr_chiral_restr0.0990.2313
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212277
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02440
LS refinement shellResolution: 2.6→2.668 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.511 38 -
Rwork0.281 806 -
all-844 -
obs--100 %

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