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

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Basic information

Entry
Database: PDB / ID: 3wyx
TitleCRYSTAL STRUCTURE OF HUMAN MPS1 CATALYTIC DOMAIN IN COMPLEX WITH 6-((3-(cyanomethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-2-(cyclohexylamino)nicotinonitrile
ComponentsDual specificity protein kinase TTK
KeywordsTRANSFERASE / KINASE / ATP Binding
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
IODIDE ION / Chem-O38 / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.9 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: Bioorg.Med.Chem. / Year: 2015
Title: A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity.
Authors: 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. / ...Authors: 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. / Murai, H. / Nakamura, Y.
History
DepositionSep 9, 2014Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 8, 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)37,4133
Polymers36,8581
Non-polymers5542
Water905
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)74,8266
Polymers73,7172
Non-polymers1,1094
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,-y,z1
Buried area2100 Å2
ΔGint-17 kcal/mol
Surface area22760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.250, 105.570, 113.380
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 (TTK) Kinase, UNP residues 516-820
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-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-O38 / 6-{[3-(cyanomethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl]amino}-2-(cyclohexylamino)pyridine-3-carbonitrile


Mass: 427.502 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H25N7O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 5 / 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: 2.85 Å3/Da / Density % sol: 56.87 % / Mosaicity: 0.66 °
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1M ADA pH6.5, 0.3M potassium iodide, 12%(w/v) PEG8000, 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: Jun 8, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.9→77.263 Å / Num. all: 8121 / Num. obs: 8121 / % possible obs: 84.9 % / Redundancy: 3.9 % / Rsym value: 0.095 / Net I/σ(I): 9.5
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2.9-3.063.90.5821.3469712140.3060.5821.987.9
3.06-3.243.80.3492.2439611440.1840.3493.287.9
3.24-3.473.90.213.7406310430.110.215.186.7
3.47-3.743.90.1295.8387110000.0680.1297.985.9
3.74-4.140.091835528960.0480.0911184.8
4.1-4.593.90.0768.631427980.040.07614.683.8
4.59-5.2940.0689.828517190.0350.06816.583.4
5.29-6.4840.0719.323605950.0370.07115.280.8
6.48-9.173.90.05510.517504530.0290.05520.179
9.17-38.6313.50.0569.18962590.0330.0562674.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation35.58 Å3 Å
Translation35.58 Å3 Å

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.20data scaling
MOLREPphasing
REFMAC5.7.0029refinement
PDB_EXTRACT3.15data extraction
CrystalCleardata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→20 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.868 / WRfactor Rfree: 0.2693 / WRfactor Rwork: 0.2261 / FOM work R set: 0.7942 / SU B: 16.491 / SU ML: 0.313 / SU Rfree: 0.4371 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.437 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2725 395 4.9 %RANDOM
Rwork0.2317 ---
obs0.2337 7718 83.79 %-
all-7718 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 124.52 Å2 / Biso mean: 67.79 Å2 / Biso min: 30.57 Å2
Baniso -1Baniso -2Baniso -3
1--6.13 Å20 Å2-0 Å2
2--6.61 Å2-0 Å2
3----0.47 Å2
Refinement stepCycle: LAST / Resolution: 2.9→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1992 0 33 5 2030
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192070
X-RAY DIFFRACTIONr_bond_other_d0.0010.021912
X-RAY DIFFRACTIONr_angle_refined_deg1.0561.9792816
X-RAY DIFFRACTIONr_angle_other_deg0.71134381
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0885255
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.27425.17287
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.26715332
X-RAY DIFFRACTIONr_dihedral_angle_4_deg30.579156
X-RAY DIFFRACTIONr_chiral_restr0.0550.2316
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212340
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02461
LS refinement shellResolution: 2.9→2.974 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.453 32 -
Rwork0.337 573 -
all-605 -
obs--87.55 %

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