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

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Basic information

Entry
Database: PDB / ID: 5eho
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-5O1 / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.18 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

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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)36,6233
Polymers36,1151
Non-polymers5082
Water1,20767
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area210 Å2
ΔGint1 kcal/mol
Surface area12030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.945, 105.486, 111.692
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 / Fragment: UNP residues 519-808
Source method: isolated from a genetically manipulated source
Details: N8-cyclohexyl-N2-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrido[3,4-d]pyrimidine-2,8-diamine
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-5O1 / ~{N}8-cyclohexyl-~{N}2-[2-methoxy-4-(1-methylpyrazol-4-yl)phenyl]pyrido[3,4-d]pyrimidine-2,8-diamine


Mass: 429.517 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27N7O
#3: 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
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 67 / 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: 2.9 Å3/Da / Density % sol: 57.63 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M BIS-TRIS Propane pH 7.5, 0.1M Sodium formate, 0.1M MgCl2, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 4r / 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: 2.18→40.52 Å / Num. obs: 22262 / % possible obs: 100 % / Redundancy: 2.7 % / Biso Wilson estimate: 55.3 Å2 / Net I/σ(I): 10.5

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.18→40.52 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.9482 / SU R Cruickshank DPI: 0.162 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.162 / SU Rfree Blow DPI: 0.138 / SU Rfree Cruickshank DPI: 0.139
RfactorNum. reflection% reflectionSelection details
Rfree0.2069 1082 4.86 %RANDOM
Rwork0.1897 ---
obs0.1905 22261 99.98 %-
Displacement parametersBiso mean: 64.37 Å2
Baniso -1Baniso -2Baniso -3
1-5.8855 Å20 Å20 Å2
2---11.0684 Å20 Å2
3---5.183 Å2
Refine analyzeLuzzati coordinate error obs: 0.297 Å
Refinement stepCycle: 1 / Resolution: 2.18→40.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2025 0 36 67 2128
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012110HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.082865HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d711SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes52HARMONIC2
X-RAY DIFFRACTIONt_gen_planes324HARMONIC5
X-RAY DIFFRACTIONt_it2110HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.07
X-RAY DIFFRACTIONt_other_torsion19.01
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion281SEMIHARMONIC5
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_contact2476SEMIHARMONIC4
LS refinement shellResolution: 2.18→2.29 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2323 135 4.58 %
Rwork0.2252 2813 -
all0.2256 2948 -
obs--99.97 %
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)
16.26410.1777-1.8538.2121-1.60866.3244-0.0657-0.5442-0.3281-0.07230.0252-0.5442-0.00570.35740.0405-0.1292-0.04520.01110.08360.0591-0.201510.275-30.5556-7.9382
28.17392.91041.72480.3277-0.21142.7496-0.1315-0.4905-0.37140.1093-0.0125-0.1351-0.1956-0.18480.144-0.05760.0030.0498-0.05030.0485-0.11962.7975-30.0796-17.4606
36.62861.10790.57771.42970.0432.5612-0.0565-0.49440.2331-0.0927-0.06420.2334-0.3201-0.38510.1207-0.14410.0403-0.03590.0420.0662-0.0429-13.1791-31.2358-22.4531
44.27651.15231.17352.63711.75458.08640.1653-0.4783-0.5442-0.0369-0.0847-0.06630.25790.3827-0.0806-0.14670.0156-0.016-0.01840.1128-0.0506-2.4679-39.2725-23.6518
51.0989-1.15690.14953.4653-0.36932.24330.0707-0.131-0.5442-0.1132-0.00560.48940.3674-0.5442-0.0651-0.1553-0.0774-0.0727-0.02390.06670.0654-16.0259-44.5985-28.7628
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|516 - 561}
2X-RAY DIFFRACTION2{A|562 - 620}
3X-RAY DIFFRACTION3{A|621 - 641}
4X-RAY DIFFRACTION4{A|642 - 712}
5X-RAY DIFFRACTION5{A|713 - 794}

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