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

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Basic information

Entry
Database: PDB / ID: 5ehl
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 / 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-0SQ / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.66 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: To Be Published
Title: Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 (MPS1) Using a Structure-Based Hydridization Approach
Authors: 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 ...Authors: 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.
History
DepositionOct 28, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Nov 9, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 30, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Apr 4, 2018Group: Data collection / Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name
Revision 1.3May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)36,3882
Polymers36,1151
Non-polymers2721
Water57632
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.130, 105.180, 112.760
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: [3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea
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-0SQ / 1-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea


Mass: 272.346 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H20N4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / 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: 2.93 Å3/Da / Density % sol: 58.02 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1M Bis Tris propane pH 7.5 0.2M MgCl2 0.2M Sodium formate 25% PEG3350
PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.91999 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Feb 7, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91999 Å / Relative weight: 1
ReflectionResolution: 2.66→60.16 Å / Num. obs: 12032 / % possible obs: 96.3 % / Redundancy: 3.7 % / Biso Wilson estimate: 78.8 Å2 / Net I/σ(I): 4.9
Reflection shellResolution: 2.66→2.79 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.56 / Mean I/σ(I) obs: 1.9 / % possible all: 98.6

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 2.66→60.16 Å / Cor.coef. Fo:Fc: 0.9413 / Cor.coef. Fo:Fc free: 0.9351 / SU R Cruickshank DPI: 0.373 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.374 / SU Rfree Blow DPI: 0.241 / SU Rfree Cruickshank DPI: 0.244
RfactorNum. reflection% reflectionSelection details
Rfree0.2192 578 4.83 %RANDOM
Rwork0.1888 ---
obs0.1903 11966 95.73 %-
Displacement parametersBiso mean: 70.46 Å2
Baniso -1Baniso -2Baniso -3
1-5.6768 Å20 Å20 Å2
2---13.1802 Å20 Å2
3---7.5034 Å2
Refine analyzeLuzzati coordinate error obs: 0.325 Å
Refinement stepCycle: 1 / Resolution: 2.66→60.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1993 0 20 32 2045
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012059HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.132806HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d679SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC2
X-RAY DIFFRACTIONt_gen_planes310HARMONIC5
X-RAY DIFFRACTIONt_it2059HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.56
X-RAY DIFFRACTIONt_other_torsion20.34
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion282SEMIHARMONIC5
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_contact2249SEMIHARMONIC4
LS refinement shellResolution: 2.66→2.91 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2618 146 5.07 %
Rwork0.2268 2731 -
all0.2285 2877 -
obs--97.99 %
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)
16.75160.56690.28872.4576-0.17464.8763-0.0513-0.5442-0.36360.2035-0.2449-0.0907-0.23160.33440.2962-0.1958-0.11390.0529-0.08970.0393-0.03649.1062-28.9602-14.4913
25.63590.94071.53323.8111-0.51913.71760.0786-0.5436-0.53560.1215-0.16780.1660.1054-0.14890.0892-0.2714-0.02210.0201-0.10590.10850.0091-8.3437-38.2565-23.2023
31.3801-0.7885-0.37274.8065-0.27532.86570.05620.158-0.5442-0.0641-0.12710.26050.4254-0.54290.0708-0.2957-0.0796-0.0961-0.10320.0260.2165-16.9258-45.4464-30.632
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|516 - 602}
2X-RAY DIFFRACTION2{A|603 - 729}
3X-RAY DIFFRACTION3{A|730 - 794}

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