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- PDB-6b4w: TTK in Complex with Inhibitor -

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Basic information

Entry
Database: PDB / ID: 6b4w
TitleTTK in Complex with Inhibitor
ComponentsDual specificity protein kinase TTK
KeywordsSIGNALING PROTEIN / Protein kinase
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 / kinetochore / spindle / 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
CACODYLATE ION / Chem-CQ7 / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.9 Å
AuthorsDelker, S. / Chamberlain, P.P.
CitationJournal: J. Med. Chem. / Year: 2017
Title: The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen.
Authors: Riggs, J.R. / Nagy, M. / Elsner, J. / Erdman, P. / Cashion, D. / Robinson, D. / Harris, R. / Huang, D. / Tehrani, L. / Deyanat-Yazdi, G. / Narla, R.K. / Peng, X. / Tran, T. / Barnes, L. / ...Authors: Riggs, J.R. / Nagy, M. / Elsner, J. / Erdman, P. / Cashion, D. / Robinson, D. / Harris, R. / Huang, D. / Tehrani, L. / Deyanat-Yazdi, G. / Narla, R.K. / Peng, X. / Tran, T. / Barnes, L. / Miller, T. / Katz, J. / Tang, Y. / Chen, M. / Moghaddam, M.F. / Bahmanyar, S. / Pagarigan, B. / Delker, S. / LeBrun, L. / Chamberlain, P.P. / Calabrese, A. / Canan, S.S. / Leftheris, K. / Zhu, D. / Boylan, J.F.
History
DepositionSep 27, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 25, 2017Provider: repository / Type: Initial release
Revision 2.0Nov 22, 2017Group: Database references / Polymer sequence / Category: citation / citation_author / entity_poly
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name / _entity_poly.pdbx_target_identifier
Revision 2.1Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)35,5223
Polymers34,8731
Non-polymers6502
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area270 Å2
ΔGint3 kcal/mol
Surface area13020 Å2
2
A: Dual specificity protein kinase TTK
hetero molecules

A: Dual specificity protein kinase TTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,0456
Polymers69,7462
Non-polymers1,2994
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_565-x,-y+1,z1
Buried area1780 Å2
ΔGint-15 kcal/mol
Surface area24800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.351, 109.581, 114.401
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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


Mass: 34872.914 Da / Num. of mol.: 1 / Fragment: UNP residues 515-795
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-CQ7 / 4-{[4-(cyclopentyloxy)-5-(2-methyl-1,3-benzoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methoxy-N-methylbenzamide


Mass: 512.560 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H28N6O4
#3: Chemical ChemComp-CAC / CACODYLATE ION / dimethylarsinate / Cacodylic acid


Mass: 136.989 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6AsO2

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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: 3.21 Å3/Da / Density % sol: 61.64 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 100mM Sodium Cacodylate, 200mM Potassium Thiocyanate, 15% PEG 4K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9795 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Feb 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.9→50.01 Å / Num. obs: 10272 / % possible obs: 99.9 % / Redundancy: 5.2 % / Net I/σ(I): 14

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Processing

Software
NameVersionClassification
REFMAC5.8.0107refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementResolution: 2.9→50.01 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.892 / SU B: 14.587 / SU ML: 0.275 / Cross valid method: THROUGHOUT / ESU R: 0.724 / ESU R Free: 0.348 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25313 498 4.9 %RANDOM
Rwork0.19126 ---
obs0.19433 9763 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 60.947 Å2
Baniso -1Baniso -2Baniso -3
1--5.16 Å20 Å20 Å2
2--2.38 Å20 Å2
3---2.79 Å2
Refinement stepCycle: 1 / Resolution: 2.9→50.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2073 0 43 0 2116
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0192167
X-RAY DIFFRACTIONr_bond_other_d0.0020.022077
X-RAY DIFFRACTIONr_angle_refined_deg1.6141.962936
X-RAY DIFFRACTIONr_angle_other_deg0.9192.9914759
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5545256
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.56525.47495
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.30515390
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.594156
X-RAY DIFFRACTIONr_chiral_restr0.2230.2320
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212396
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02461
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.6226.0171033
X-RAY DIFFRACTIONr_mcbond_other4.6246.0181032
X-RAY DIFFRACTIONr_mcangle_it7.0299.0191286
X-RAY DIFFRACTIONr_mcangle_other7.0269.0181287
X-RAY DIFFRACTIONr_scbond_it4.8966.3121134
X-RAY DIFFRACTIONr_scbond_other4.8946.3131135
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.5969.2971651
X-RAY DIFFRACTIONr_long_range_B_refined10.67446.9042449
X-RAY DIFFRACTIONr_long_range_B_other10.71246.8642424
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.341 40 -
Rwork0.268 693 -
obs--100 %

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