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- PDB-3wzj: CRYSTAL STRUCTURE OF HUMAN MPS1 CATALYTIC DOMAIN IN COMPLEX WITH ... -

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Basic information

Entry
Database: PDB / ID: 3wzj
TitleCRYSTAL STRUCTURE OF HUMAN MPS1 CATALYTIC DOMAIN IN COMPLEX WITH 4-(6-(cyclohexylamino)-8-(((tetrahydro-2H-pyran-4-yl)methyl)amino)imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropylbenzamide
ComponentsDual specificity protein kinase TTK
KeywordsTRANSFERASE / ATP Binding / Phosphorylation
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-O43 / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.75 Å
AuthorsKusakabe, K. / Ide, N. / Daigo, Y. / Itoh, T. / Yamamoto, T. / Kojima, E. / Mitsuoka, Y. / Tadano, G. / Tagashira, S. / Higashino, K. ...Kusakabe, K. / Ide, N. / Daigo, Y. / Itoh, T. / Yamamoto, T. / Kojima, E. / Mitsuoka, Y. / Tadano, G. / Tagashira, S. / Higashino, K. / Okano, Y. / Sato, Y. / Inoue, M. / Iguchi, M. / Kanazawa, T. / Ishioka, Y. / Dohi, K. / Kido, Y. / Sakamoto, S. / Ando, S. / Maeda, M. / Higaki, M. / Yoshizawa, H. / Mura, H. / Nakamura, Y.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Authors: Kusakabe, K. / Ide, N. / Daigo, Y. / Itoh, T. / Yamamoto, T. / Hashizume, H. / Nozu, K. / Yoshida, H. / Tadano, G. / Tagashira, S. / Higashino, K. / Okano, Y. / Sato, Y. / Inoue, M. / ...Authors: Kusakabe, K. / Ide, N. / Daigo, Y. / Itoh, T. / Yamamoto, T. / Hashizume, H. / Nozu, K. / Yoshida, H. / Tadano, G. / Tagashira, S. / Higashino, K. / Okano, Y. / Sato, Y. / Inoue, M. / Iguchi, M. / Kanazawa, T. / Ishioka, Y. / Dohi, K. / Kido, Y. / Sakamoto, S. / Ando, S. / Maeda, M. / Higaki, M. / Baba, Y. / Nakamura, Y.
History
DepositionSep 29, 2014Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 11, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Refinement description / Category: software
Revision 1.2Aug 24, 2022Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / database_2 / struct_ref_seq_dif / struct_site
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dual specificity protein kinase TTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3472
Polymers36,8581
Non-polymers4891
Water362
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Dual specificity protein kinase TTK
hetero molecules

A: Dual specificity protein kinase TTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,6944
Polymers73,7172
Non-polymers9772
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,-y,z1
Buried area1280 Å2
ΔGint-13 kcal/mol
Surface area23700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.961, 110.389, 114.356
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 36858.363 Da / Num. of mol.: 1 / Fragment: MPS1 KINASE DOMAIN, UNP residues 516-820
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTK, MPS1, MPS1L1 / Production host: CELL-FREE SYNTHESIS (others) / References: UniProt: P33981, dual-specificity kinase
#2: Chemical ChemComp-O43 / 4-{6-(cyclohexylamino)-8-[(tetrahydro-2H-pyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropylbenzamide


Mass: 488.624 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H36N6O2
#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: 3.04 Å3/Da / Density % sol: 59.51 % / Mosaicity: 0.67 °
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1M Tris hydrochloride pH7.5, 0.12M magnesium chloride, 8%(w/v) triethylene glycol , VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jul 31, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.75→50 Å / Num. all: 12038 / Num. obs: 10489 / % possible obs: 87.2 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.062 / Χ2: 1.156 / Net I/σ(I): 12.6
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.75-2.83.20.445310.86688.9
2.8-2.853.10.445070.89787
2.85-2.93.20.3945310.95688.9
2.9-2.963.30.3254930.87584.6
2.96-3.033.30.2715240.97387.9
3.03-3.13.30.285170.985.6
3.1-3.173.30.2095141.04589.9
3.17-3.263.40.1615271.07687.7
3.26-3.363.50.1385191.04487.2
3.36-3.463.50.1225421.17888.9
3.46-3.593.50.1015171.20689.3
3.59-3.733.60.0795321.17488.2
3.73-3.93.60.0685271.21288.4
3.9-4.113.60.0575221.32387.7
4.11-4.363.70.0525451.48388.9
4.36-4.73.80.0455181.4387.2
4.7-5.173.90.0435331.3887.4
5.17-5.923.70.0475201.35284.8
5.92-7.463.70.0365281.22184.5
7.46-503.50.0215421.20181.4

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3 Å33.58 Å
Translation33.58 Å3 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMAC5.7.0029refinement
PDB_EXTRACT3.15data extraction
CrystalCleardata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.75→20 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.91 / WRfactor Rfree: 0.2565 / WRfactor Rwork: 0.1966 / FOM work R set: 0.7788 / SU B: 14.237 / SU ML: 0.285 / SU R Cruickshank DPI: 0.8407 / SU Rfree: 0.3913 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.841 / ESU R Free: 0.391 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.282 1016 9.7 %RANDOM
Rwork0.2205 ---
obs0.2268 9466 87.03 %-
all-12042 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 118.02 Å2 / Biso mean: 63.813 Å2 / Biso min: 25.73 Å2
Baniso -1Baniso -2Baniso -3
1--2.77 Å2-0 Å20 Å2
2--5.16 Å20 Å2
3----2.39 Å2
Refinement stepCycle: LAST / Resolution: 2.75→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2015 0 36 2 2053
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192099
X-RAY DIFFRACTIONr_angle_refined_deg1.21.9822853
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5565254
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.14925.69993
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.35315349
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.646155
X-RAY DIFFRACTIONr_chiral_restr0.0750.2317
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211577
LS refinement shellResolution: 2.75→2.82 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.392 74 -
Rwork0.322 681 -
all-755 -
obs--87.38 %

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