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- PDB-5ei8: Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopola... -

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Basic information

Entry
Database: PDB / ID: 5ei8
TitleRapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 (MPS1) Using a Structure-Based Hydridization Approach
ComponentsDual specificity protein kinase TTK
KeywordsTRANSFERASE / Spindle Assembly Checkpoint (SAC) / Oncology target Pyrido[3 / 4-d]pyrimidine based inhibitors Selective against MPS1
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-5OE / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.17 Å
AuthorsInnocenti, P. / Woodward, H.L. / Solanki, S. / Naud, N. / Westwood, I.M. / Cronin, N. / Hayes, A. / Roberts, J. / Henley, A.T. / Baker, R. ...Innocenti, P. / Woodward, H.L. / Solanki, S. / Naud, N. / Westwood, I.M. / Cronin, N. / Hayes, A. / Roberts, J. / Henley, A.T. / Baker, R. / Faisal, A. / Mak, G. / Box, G. / Valenti, M. / De Haven Brandon, A. / O'Fee, L. / Saville, J. / Schmitt, J. / Burke, R. / van Montfort, R.L.M. / Raymaud, F.I. / Eccles, S.A. / Linardopoulos, S. / Blagg, J. / Hoelder, S.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UK United Kingdom
CitationJournal: J.Med.Chem. / Year: 2016
Title: Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.
Authors: Innocenti, P. / Woodward, H.L. / Solanki, S. / Naud, S. / Westwood, I.M. / Cronin, N. / Hayes, A. / Roberts, J. / Henley, A.T. / Baker, R. / Faisal, A. / Mak, G.W. / Box, G. / Valenti, M. / ...Authors: Innocenti, P. / Woodward, H.L. / Solanki, S. / Naud, S. / Westwood, I.M. / Cronin, N. / Hayes, A. / Roberts, J. / Henley, A.T. / Baker, R. / Faisal, A. / Mak, G.W. / Box, G. / Valenti, M. / De Haven Brandon, A. / O'Fee, L. / Saville, H. / Schmitt, J. / Matijssen, B. / Burke, R. / van Montfort, R.L. / Raynaud, F.I. / Eccles, S.A. / Linardopoulos, S. / Blagg, J. / Hoelder, S.
History
DepositionOct 29, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Apr 20, 2016Provider: repository / Type: Initial release
Revision 1.1May 11, 2016Group: Database references
Revision 1.2Aug 30, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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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)36,7625
Polymers36,1151
Non-polymers6474
Water72140
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area650 Å2
ΔGint6 kcal/mol
Surface area12370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.003, 101.983, 110.868
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 36115.258 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine
Source: (gene. exp.) Homo sapiens (human) / Gene: TTK, MPS1, MPS1L1 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P33981, dual-specificity kinase
#2: Chemical ChemComp-5OE / ~{N}-[2-methoxy-4-(1-methylpyrazol-4-yl)phenyl]-8-(1-methylpyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine


Mass: 412.447 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20N8O
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 40 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.77 Å3/Da / Density meas: 55.61 Mg/m3 / Density % sol: 55.1 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M BIS-TRIS Propane 0.2 M NgCl2 0.2 M Sodium formate 20 % PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Mar 16, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.17→39.98 Å / Num. obs: 21262 / % possible obs: 99.6 % / Redundancy: 21.6 % / Biso Wilson estimate: 41.97 Å2 / Net I/σ(I): 8.9

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 2.17→37.53 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.9387 / SU R Cruickshank DPI: 0.193 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.191 / SU Rfree Blow DPI: 0.167 / SU Rfree Cruickshank DPI: 0.169
RfactorNum. reflection% reflectionSelection details
Rfree0.2441 1092 5.22 %RANDOM
Rwork0.2141 ---
obs0.2157 20909 99.18 %-
Displacement parametersBiso mean: 64.52 Å2
Baniso -1Baniso -2Baniso -3
1-5.2267 Å20 Å20 Å2
2--3.4311 Å20 Å2
3----8.6578 Å2
Refine analyzeLuzzati coordinate error obs: 0.405 Å
Refinement stepCycle: 1 / Resolution: 2.17→37.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2040 0 43 40 2123
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012130HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.092894HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d704SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes52HARMONIC2
X-RAY DIFFRACTIONt_gen_planes333HARMONIC5
X-RAY DIFFRACTIONt_it2130HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.95
X-RAY DIFFRACTIONt_other_torsion19.6
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion286SEMIHARMONIC5
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_contact2419SEMIHARMONIC4
LS refinement shellResolution: 2.17→2.29 Å
RfactorNum. reflection% reflection
Rfree0.2391 145 5.27 %
Rwork0.224 2604 -
obs--99.93 %
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)
18.31552.7143-2.62617.8239-0.74997.8355-0.0737-0.5442-0.21240.5437-0.0232-0.4511-0.01960.05320.0969-0.1386-0.0396-0.04530.14970.1514-0.285310.3827-30.2962-7.573
25.49270.77872.80221.3288-0.64665.36330.00380.3161-0.257-0.0620.1699-0.1226-0.1051-0.1106-0.1737-0.304-0.12920.01220.3040.152-0.04928.7834-27.87-24.9652
38.22731.24732.91042.989-0.37632.9750.0716-0.1130.290.21950.0673-0.053-0.2167-0.5017-0.1389-0.1221-0.01980.07930.27840.1402-0.26870.4192-30.7919-14.0803
47.23711.76742.10835.2703-1.33995.9138-0.00090.16090.092-0.1431-0.19340.1681-0.25620.04480.1943-0.3040.0779-0.02860.28020.152-0.1274-13.0317-30.3928-22.6143
58.07221.01011.4294.43260.61945.17310.18790.2724-0.28320.21560.0037-0.11520.0070.0399-0.1916-0.304-0.03020.0030.3040.152-0.2803-2.0653-37.6187-21.1294
61.0849-0.74392.26836.0132-1.65900.0240.1345-0.3922-0.28610.00770.06920.25460.0275-0.0317-0.304-0.0278-0.02590.3040.1008-0.2904-9.503-42.0434-31.2203
74.7947-1.59861.06244.2683-0.57621.368-0.03440.1119-0.227-0.17360.18110.45970.5365-0.0304-0.1467-0.2399-0.1236-0.03910.28890.0769-0.1478-13.8837-52.2022-29.5712
84.8598-2.06412.91044.8641-2.8690-0.01320.4162-0.117-0.20930.13070.51820.1571-0.2655-0.1174-0.304-0.0183-0.0690.3040.152-0.1469-19.7007-35.8088-31.3368
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|516 - 561}
2X-RAY DIFFRACTION2{A|562 - 580}
3X-RAY DIFFRACTION3{A|581 - 620}
4X-RAY DIFFRACTION4{A|621 - 641}
5X-RAY DIFFRACTION5{A|642 - 691}
6X-RAY DIFFRACTION6{A|692 - 729}
7X-RAY DIFFRACTION7{A|730 - 761}
8X-RAY DIFFRACTION8{A|762 - 794}

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