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

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Basic information

Entry
Database: PDB / ID: 5ehy
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-5O4 / Chem-7PE / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.26 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)38,93815
Polymers36,1151
Non-polymers2,82214
Water82946
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3250 Å2
ΔGint10 kcal/mol
Surface area12930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.616, 111.453, 113.694
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Protein , 1 types, 1 molecules A

#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: 4-(furan-3-yl)-3-phenyl-1H-pyrazolo[4,3-c]pyridine / Source: (gene. exp.) Homo sapiens (human) / Gene: TTK, MPS1, MPS1L1 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P33981, dual-specificity kinase

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Non-polymers , 5 types, 60 molecules

#2: Chemical
ChemComp-7PE / 2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL / POLYETHYLENE GLYCOL FRAGMENT / Polyethylene glycol


Mass: 310.384 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C14H30O7
#3: Chemical ChemComp-5O4 / 4-(furan-3-yl)-3-phenyl-2~{H}-pyrazolo[4,3-c]pyridine


Mass: 261.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H11N3O
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


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


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


Mass: 18.015 Da / Num. of mol.: 46 / 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: 3.11 Å3/Da / Density % sol: 60.42 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1m HEPES pH 7.5 30-45% PEG300

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9763 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Aug 4, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.26→41.15 Å / Num. obs: 21345 / % possible obs: 99.7 % / Redundancy: 4.3 % / Biso Wilson estimate: 59.99 Å2 / Net I/σ(I): 7.7

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 2.26→24.2 Å / Cor.coef. Fo:Fc: 0.9545 / Cor.coef. Fo:Fc free: 0.948 / SU R Cruickshank DPI: 0.174 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.173 / SU Rfree Blow DPI: 0.148 / SU Rfree Cruickshank DPI: 0.15
RfactorNum. reflection% reflectionSelection details
Rfree0.2072 1071 5.02 %RANDOM
Rwork0.1854 ---
obs0.1865 21324 99.67 %-
Displacement parametersBiso mean: 73.41 Å2
Baniso -1Baniso -2Baniso -3
1-10.6828 Å20 Å20 Å2
2---0.8109 Å20 Å2
3----9.8719 Å2
Refine analyzeLuzzati coordinate error obs: 0.332 Å
Refinement stepCycle: 1 / Resolution: 2.26→24.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2020 0 117 46 2183
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012172HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.132907HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d766SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes55HARMONIC2
X-RAY DIFFRACTIONt_gen_planes317HARMONIC5
X-RAY DIFFRACTIONt_it2172HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.86
X-RAY DIFFRACTIONt_other_torsion18.17
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion280SEMIHARMONIC5
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_contact2465SEMIHARMONIC4
LS refinement shellResolution: 2.26→2.37 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2337 137 4.97 %
Rwork0.235 2620 -
all0.2349 2757 -
obs--97.55 %
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)
18.31552.8739-1.44657.1074-0.11613.54940.020.5442-0.5442-0.29750.2078-0.24070.46810.4694-0.2278-0.12360.0036-0.0242-0.1569-0.150.10345.7987119.992134.442
26.4295-2.58461.55931.72170.37041.77120.12040.158-0.5118-0.0652-0.06660.08360.0859-0.1282-0.0538-0.1725-0.02780.0249-0.1469-0.05870.034132.7526131.59135.449
31.34770.38482.31420-1.08144.07730.01180.4296-0.0041-0.1170.0397-0.2742-0.0330.105-0.0515-0.09920.01940.03810.06790.02990.110633.8413143.631125.863
42.85880.2520.26222.74220.34535.4459-0.00440.54420.3198-0.5442-0.23980.2479-0.4607-0.53980.2442-0.14450.1042-0.0860.0104-0.0177-0.017419.841144.221121.329
51.5258-0.3398-2.810302.90810.0477-0.00670.09410.02250.0163-0.07440.0722-0.0007-0.10490.0811-0.21160.0117-0.0378-0.0181-0.1130.182113.2077139.951137.325
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|515 - 561}
2X-RAY DIFFRACTION2{A|562 - 662}
3X-RAY DIFFRACTION3{A|663 - 712}
4X-RAY DIFFRACTION4{A|713 - 781}
5X-RAY DIFFRACTION5{A|782 - 794}

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