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- PDB-4cva: MPS1 kinase with 3-aminopyridin-2-one inhibitors -

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Basic information

Entry
Database: PDB / ID: 4cva
TitleMPS1 kinase with 3-aminopyridin-2-one inhibitors
ComponentsDUAL SPECIFICITY PROTEIN KINASE TTK
KeywordsTRANSFERASE / FRAGMENT / INHIBITOR
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-WBI / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsFearon, D. / Bavetsias, V. / Bayliss, R. / Schmitt, J. / Westwood, I.M. / vanMontfort, R.L.M. / Jones, K.
CitationJournal: To be Published
Title: Protein Kinase Selectivity of a 3-Aminopyridin-2- One Based Fragment Library, Identification of 3-Amino-5-(Pyridin-4-Yl)Pyridin-2(1H)-One as a Novel Scaffold for Mps1 Inhibition
Authors: Fearon, D. / Bavetsias, V. / Bayliss, R. / Schmitt, J. / Westwood, I.M. / Van Montfort, R.L.M. / Jones, K.
History
DepositionMar 24, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 8, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _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)36,8506
Polymers36,1951
Non-polymers6555
Water50428
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)70.460, 107.160, 112.750
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-2003-

HOH

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Components

#1: Protein DUAL SPECIFICITY PROTEIN KINASE TTK / MONOPOLAR SPINDLE KINASE 1 / PHOSPHOTYROSINE PICKED THREONINE-PROTEIN KINASE / PYT


Mass: 36195.234 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 519-808
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): AI / References: UniProt: P33981, dual-specificity kinase
#2: Chemical ChemComp-WBI / N-(6-oxo-1,6-dihydro-3,4'-bipyridin-5-yl)-4-(piperidin-1-yl)benzamide


Mass: 374.436 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22N4O2
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 28 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE SEQUENCE INCLUDING HEXAHISTIDINE TAG IS AS DESCRIBED IN NAT. CHEM. BIOL. 2010, 6, 259-368.

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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: 3.61 Å3/Da / Density % sol: 65.9 % / Description: NONE
Crystal growpH: 7.5
Details: 0.2M NACO2H, 0.1M BTP PH 7.5, 15% W/V PEG3350, 1% DMSO AND 1MM (N-(2-OXO-5-(PYRIDIN-4-YL)-1, 2-DIHYDROPYRIDIN-3-YL)-4-PIPERIDIN-1-YL)BENZAMIDE.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9795
DetectorType: ADSC QUANTUM / Detector: CCD / Date: Apr 21, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.5→40.72 Å / Num. obs: 15117 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 4.4 % / Biso Wilson estimate: 71.72 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 10.7
Reflection shellResolution: 2.5→2.6 Å / Redundancy: 4.5 % / Mean I/σ(I) obs: 0.8 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2ZMC

2zmc


Resolution: 2.5→39.89 Å / Cor.coef. Fo:Fc: 0.9514 / Cor.coef. Fo:Fc free: 0.9355 / SU R Cruickshank DPI: 0.255 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.253 / SU Rfree Blow DPI: 0.194 / SU Rfree Cruickshank DPI: 0.197
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.215 760 5.03 %RANDOM
Rwork0.1897 ---
obs0.1909 15108 99.82 %-
Displacement parametersBiso mean: 76.55 Å2
Baniso -1Baniso -2Baniso -3
1-2.2546 Å20 Å20 Å2
2---0.073 Å20 Å2
3----2.1816 Å2
Refine analyzeLuzzati coordinate error obs: 0.365 Å
Refinement stepCycle: LAST / Resolution: 2.5→39.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1963 0 44 28 2035
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012049HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.082782HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d677SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes45HARMONIC2
X-RAY DIFFRACTIONt_gen_planes316HARMONIC5
X-RAY DIFFRACTIONt_it2049HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.7
X-RAY DIFFRACTIONt_other_torsion19.84
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion277SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2327SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.67 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2953 142 5.26 %
Rwork0.2322 2557 -
all0.2354 2699 -
obs--99.82 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
17.9344-1.07392.88473.4451-1.56588.31550.0230.22580.1303-0.0741-0.053-0.3172-0.08620.35850.0299-0.28940.0684-0.00840.3040.0303-0.3049.9533-23.7816-48.7018
24.9925-1.6218-1.31861.45690.38963.52090.0480.39740.1023-0.0497-0.05150.1446-0.0321-0.19840.0035-0.2829-0.0112-0.00380.26130.0611-0.2901-2.2583-22.2728-37.1552
30.61310.00840.14862.611-0.6452.87740.2830.15360.54420.1334-0.08970.1634-0.5442-0.4241-0.1933-0.30030.08140.13710.240.0768-0.084-13.0217-8.8349-28.1189
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A AND RESI 516 - 561
2X-RAY DIFFRACTION2CHAIN A AND RESI 562 - 662
3X-RAY DIFFRACTION3CHAIN A AND RESI 663 - 794

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