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- PDB-7cil: Crystal structure of TTK kinase domain in complex with compound 7 -

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Basic information

Entry
Database: PDB / ID: 7cil
TitleCrystal structure of TTK kinase domain in complex with compound 7
ComponentsDual specificity protein kinase TTK
KeywordsTRANSFERASE / Kinase MPS1 TTK Structure-guided drug design
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 / 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
Similarity search - Domain/homology
Chem-FZR / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsKim, H.L. / Cho, H.Y. / Park, Y.W. / Lee, Y.H. / Son, J.B. / Ko, E.H. / Choi, H.G. / Kim, N.D.
CitationJournal: J.Med.Chem. / Year: 2021
Title: X-ray Crystal Structure-Guided Design and Optimization of 7 H -Pyrrolo[2,3- d ]pyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor.
Authors: Lee, Y. / Kim, H. / Kim, H. / Cho, H.Y. / Jee, J.G. / Seo, K.A. / Son, J.B. / Ko, E. / Choi, H.G. / Kim, N.D. / Kim, I.
History
DepositionJul 7, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 12, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 9, 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 1.2Nov 29, 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

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Assembly

Deposited unit
A: Dual specificity protein kinase TTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8762
Polymers32,5391
Non-polymers3361
Water45025
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13400 Å2
Unit cell
Length a, b, c (Å)70.458, 110.175, 113.142
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: x+1/2,-y+1/2,-z+1/2
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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Components

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


Mass: 32539.279 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-FZR / 4-(cyclohexylamino)-2-[(1-methylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile


Mass: 336.394 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20N8 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 25 / 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: 3.49 Å3/Da / Density % sol: 64.76 %
Crystal growTemperature: 294.15 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 7-9% PEG 10000, 0.08-0.14 M magnesium acetate, 0.1 M MES pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PAL/PLS / Beamline: 5C (4A) / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 31, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 19865 / % possible obs: 99.9 % / Redundancy: 6.6 % / Biso Wilson estimate: 62.99 Å2 / CC1/2: 0.987 / Net I/σ(I): 47.265
Reflection shellResolution: 2.3→2.34 Å / Num. unique obs: 132016 / CC1/2: 0.913

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6B4W

6b4w


Resolution: 2.3→40.95 Å / SU ML: 0.2757 / Cross valid method: NONE / σ(F): 1.36 / Phase error: 28.6755 / Stereochemistry target values: CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2461 1997 10.06 %
Rwork0.2097 17861 -
obs0.2134 19858 99.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 76.93 Å2
Refinement stepCycle: LAST / Resolution: 2.3→40.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2146 0 25 25 2196
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00842226
X-RAY DIFFRACTIONf_angle_d0.9833015
X-RAY DIFFRACTIONf_chiral_restr0.0629329
X-RAY DIFFRACTIONf_plane_restr0.0065379
X-RAY DIFFRACTIONf_dihedral_angle_d5.89931899
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.360.31091410.29051254X-RAY DIFFRACTION99.36
2.36-2.420.36411420.27241241X-RAY DIFFRACTION99.93
2.42-2.50.32421400.271260X-RAY DIFFRACTION100
2.5-2.580.3131400.24961261X-RAY DIFFRACTION100
2.58-2.670.32651350.25811266X-RAY DIFFRACTION100
2.67-2.770.30421450.25221264X-RAY DIFFRACTION100
2.77-2.90.30871400.25311264X-RAY DIFFRACTION99.93
2.9-3.050.28321450.25631274X-RAY DIFFRACTION100
3.05-3.250.30521400.24941267X-RAY DIFFRACTION100
3.25-3.50.26031440.24591276X-RAY DIFFRACTION100
3.5-3.850.27831410.21281281X-RAY DIFFRACTION100
3.85-4.40.2191440.18381301X-RAY DIFFRACTION99.93
4.4-5.550.1971460.17811296X-RAY DIFFRACTION100
5.55-40.950.21461540.18611356X-RAY DIFFRACTION98.5

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