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

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Basic information

Entry
Database: PDB / ID: 3wzk
TitleCRYSTAL STRUCTURE OF HUMAN MPS1 CATALYTIC DOMAIN IN COMPLEX WITH N-cyclopropyl-4-(8-((thiophen-2-ylmethyl)amino)imidazo[1,2-a]pyrazin-3-yl)benzamide
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 / kinetochore / spindle / protein tyrosine kinase activity / phosphorylation / 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-O23 / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 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 1.1Aug 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
Revision 1.2May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)37,2833
Polymers36,8581
Non-polymers4252
Water59433
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)74,5676
Polymers73,7172
Non-polymers8504
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
Buried area1680 Å2
ΔGint-36 kcal/mol
Surface area23630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.820, 109.350, 113.310
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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-O23 / N-cyclopropyl-4-{8-[(thiophen-2-ylmethyl)amino]imidazo[1,2-a]pyrazin-3-yl}benzamide


Mass: 389.473 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19N5OS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 33 / 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: 2.98 Å3/Da / Density % sol: 58.67 % / Mosaicity: 0.74 °
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1M PIPES pH6.5, 12.3%(w/v) PEG3350, 0.0818M magnesium sulfate, 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: Apr 16, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→78.685 Å / Num. all: 19152 / Num. obs: 19152 / % possible obs: 96.6 % / Redundancy: 4 % / Rsym value: 0.064 / Net I/σ(I): 9
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2.3-2.4240.521.41115127870.2710.522.397.2
2.42-2.5740.352.11056226390.180.353.397.9
2.57-2.7540.223.31001225190.1140.224.898.4
2.75-2.9740.1435945623430.0740.1436.998.2
2.97-3.2540.0878852421300.0460.0879.997.9
3.25-3.644.10.069.5786919420.0310.0613.297.2
3.64-4.24.10.04812.4690516840.0250.04816.394.9
4.2-5.144.20.0589.9586714130.0290.05818.193.8
5.14-7.274.10.04610453110920.0240.04617.591.9
7.27-40.433.90.03611.323476030.0210.03618.789.1

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation39.34 Å3 Å
Translation39.34 Å3 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
MOLREPphasing
REFMAC5.7.0029refinement
PDB_EXTRACT3.15data extraction
CrystalCleardata collection
iMOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→20 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.917 / SU B: 6.963 / SU ML: 0.167 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.241 / ESU R Free: 0.224 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2799 978 5.1 %RANDOM
Rwork0.2216 ---
obs0.2244 18146 95.83 %-
all-19152 --
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: 113.52 Å2 / Biso mean: 59.92 Å2 / Biso min: 32.88 Å2
Baniso -1Baniso -2Baniso -3
1--3.3 Å2-0 Å20 Å2
2--4.44 Å20 Å2
3----1.14 Å2
Refinement stepCycle: LAST / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2005 0 29 33 2067
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192081
X-RAY DIFFRACTIONr_angle_refined_deg1.2431.9782828
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9425255
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.90125.16989
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.99615342
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.26156
X-RAY DIFFRACTIONr_chiral_restr0.0830.2313
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211572
LS refinement shellResolution: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.361 75 -
Rwork0.33 1326 -
all-1401 -
obs--96.89 %

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