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- PDB-4cv9: MPS1 kinase with 3-aminopyridin-2-one inhibitors -

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Basic information

Entry
Database: PDB / ID: 4cv9
TitleMPS1 kinase with 3-aminopyridin-2-one inhibitors
ComponentsDUAL SPECIFICITY PROTEIN KINASE TTK
KeywordsTRANSFERASE / INHIBITOR
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 / 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-W2K / 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 1.1May 8, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / pdbx_seq_map_depositor_info / struct_conn
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval ..._exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval / _pdbx_seq_map_depositor_info.one_letter_code_mod / _struct_conn.pdbx_leaving_atom_flag
Revision 1.2Dec 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_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_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)36,9738
Polymers36,1951
Non-polymers7787
Water54030
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)70.380, 108.720, 113.560
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-2004-

HOH

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Components

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


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-W2K / 4-(4-Methylpiperazin-1-yl)-N-(2-oxo-5-(pyridin-4-yl)-1,2-dihydropyridin-3-yl)benzamide


Mass: 389.450 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H23N5O2
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 30 / 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: 3.69 Å3/Da / Density % sol: 66.7 % / Description: NONE
Crystal growTemperature: 291 K / pH: 7.5
Details: 0.2M NACO2H, 0.1M BTP PH 7.5, 15% W/V PEG3350, 1% DMSO AND 1MM 4-(4-METHYLPIPERAZIN-1-YL)-N-(2-OXO-5-(PYRIDIN-4-YL)-1, 2-DIHYDROPYRIDIN-3-YL)BENZAMIDE. 18 DEGREES C.

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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→40.94 Å / Num. obs: 15436 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 4.8 % / Biso Wilson estimate: 81.52 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 13.8
Reflection shellResolution: 2.5→2.6 Å / Redundancy: 5 % / Rmerge(I) obs: 1.4 / Mean I/σ(I) obs: 0.9 / % possible all: 99.9

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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→40.94 Å / Cor.coef. Fo:Fc: 0.9554 / Cor.coef. Fo:Fc free: 0.9253 / SU R Cruickshank DPI: 0.243 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.241 / SU Rfree Blow DPI: 0.207 / SU Rfree Cruickshank DPI: 0.21
RfactorNum. reflection% reflectionSelection details
Rfree0.2323 769 4.98 %RANDOM
Rwork0.1854 ---
obs0.1877 15434 99.87 %-
Displacement parametersBiso mean: 85.88 Å2
Baniso -1Baniso -2Baniso -3
1-9.5151 Å20 Å20 Å2
2---8.2569 Å20 Å2
3----1.2581 Å2
Refine analyzeLuzzati coordinate error obs: 0.402 Å
Refinement stepCycle: LAST / Resolution: 2.5→40.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1944 0 53 30 2027
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012036HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.122761HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d668SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes45HARMONIC2
X-RAY DIFFRACTIONt_gen_planes313HARMONIC5
X-RAY DIFFRACTIONt_it2036HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.87
X-RAY DIFFRACTIONt_other_torsion20.31
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion276SEMIHARMONIC5
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_contact2304SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.67 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2768 142 5.17 %
Rwork0.2507 2607 -
all0.252 2749 -
obs--99.87 %
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)
18.31551.71542.82152.0117-0.04848.3155-0.03070.37160.19240.0080.0747-0.2623-0.01270.4739-0.044-0.20330.07910.10520.304-0.0073-0.302410.7998-24.4875-51.1675
25.3442-0.98860.36820.2094-0.4837.0141-0.11970.10320.313-0.047-0.07110.0489-0.01210.54420.1908-0.20330.0649-0.02070.16880.0105-0.22838.3683-26.0438-40.3143
35.22980.15670.35582.4230.04838.07860.1320.54420.4908-0.31180.00680.1573-0.3441-0.5433-0.1387-0.3040.08040.04370.21030.1008-0.2391-9.973-19.3578-38.579
41.6210.4143-0.18882.9119-1.01953.74020.36280.01630.54420.077-0.18140.0663-0.5442-0.4631-0.1814-0.24120.12640.1520.11840.0353-0.031-13.479-9.3435-28.7284
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A AND RESI 515 - 536
2X-RAY DIFFRACTION2CHAIN A AND RESI 537 - 602
3X-RAY DIFFRACTION3CHAIN A AND RESI 603 - 662
4X-RAY DIFFRACTION4CHAIN A AND RESI 663 - 794

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