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- PDB-5eh0: Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopola... -

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Entry
Database: PDB / ID: 5eh0
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 / nucleus / identical protein binding / 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-5NW / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / 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: 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 27, 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
Revision 2.0Apr 24, 2019Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / diffrn_source / entity / entity_name_com / entity_poly / entity_poly_seq / entity_src_gen / pdbx_entity_src_syn / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / pdbx_validate_polymer_linkage / struct_conf / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _atom_site.label_seq_id / _atom_site_anisotrop.pdbx_label_seq_id ..._atom_site.label_seq_id / _atom_site_anisotrop.pdbx_label_seq_id / _diffrn_source.pdbx_synchrotron_site / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_ec / _entity.src_method / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _pdbx_unobs_or_zero_occ_atoms.label_seq_id / _struct_conf.beg_label_seq_id / _struct_conf.end_label_seq_id / _struct_ref.db_code / _struct_ref.db_name / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.seq_align_end
Revision 2.1Jul 10, 2019Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site

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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)32,7413
Polymers32,2451
Non-polymers4962
Water55831
1
A: Dual specificity protein kinase TTK
hetero molecules

A: Dual specificity protein kinase TTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,4816
Polymers64,4902
Non-polymers9914
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
Buried area2320 Å2
ΔGint-13 kcal/mol
Surface area22270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.420, 105.920, 112.210
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 32245.084 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N8-Neopentyl-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 BL21 (bacteria) / References: UniProt: P33981, dual-specificity kinase
#2: Chemical ChemComp-5NW / N2-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine


Mass: 417.507 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27N7O
#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.: 31 / Source method: isolated from a natural source / Formula: H2O

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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: 3.48 Å3/Da / Density % sol: 64.67 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M BisTris Propane pH 7.5 0.2 M MgCl2 0.2M Sodium Formate 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.968 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 29, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.968 Å / Relative weight: 1
ReflectionRedundancy: 4.4 % / Number: 97927 / Rmerge(I) obs: 0.042 / D res high: 2.18 Å / D res low: 40.54 Å / Num. obs: 22272 / % possible obs: 99.9 / Rejects: 24
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsRedundancy
2.182.2512.5554.3
8.9940.5410.023.8
ReflectionResolution: 2.18→40.54 Å / Num. obs: 22272 / % possible obs: 99.9 % / Redundancy: 4.4 % / Biso Wilson estimate: 70.46 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.042 / Rpim(I) all: 0.022 / Net I/σ(I): 11.4 / Num. measured all: 97927 / Scaling rejects: 24
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2.18-2.254.32.5550.5822118970.3741.39399.7
8.99-40.543.80.0241.413963680.9990.01199.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å40.54 Å

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Processing

Software
NameVersionClassification
Aimless0.5.7data scaling
PHASER2.5.7phasing
BUSTER-TNTrefinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.18→23.78 Å / Cor.coef. Fo:Fc: 0.9537 / Cor.coef. Fo:Fc free: 0.956 / SU R Cruickshank DPI: 0.164 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.162 / SU Rfree Blow DPI: 0.141 / SU Rfree Cruickshank DPI: 0.144
RfactorNum. reflection% reflectionSelection details
Rfree0.2165 1178 5.3 %RANDOM
Rwork0.1964 ---
obs0.1975 22237 99.88 %-
Displacement parametersBiso max: 167.75 Å2 / Biso mean: 88.21 Å2 / Biso min: 57.99 Å2
Baniso -1Baniso -2Baniso -3
1-13.3541 Å20 Å20 Å2
2---16.3806 Å20 Å2
3---3.0265 Å2
Refine analyzeLuzzati coordinate error obs: 0.351 Å
Refinement stepCycle: final / Resolution: 2.18→23.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1999 0 35 31 2065
Biso mean--84.08 83.6 -
Num. residues----258
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d690SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC2
X-RAY DIFFRACTIONt_gen_planes326HARMONIC5
X-RAY DIFFRACTIONt_it2085HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
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_contact2347SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2085HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2839HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion2.87
X-RAY DIFFRACTIONt_other_torsion18.41
LS refinement shellResolution: 2.18→2.29 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2751 165 5.65 %
Rwork0.241 2754 -
all0.2429 2919 -
obs--99.69 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
14.40111.34451.32392.3276-0.293.3169-0.0233-0.5442-0.15210.21050.02430.0518-0.1118-0.0994-0.0011-0.22380.01280.0659-0.00130.1104-0.24761.2938-31.5997-16.2065
21.8679-1.0989-0.23422.7661-0.40563.67490.0509-0.0926-0.5442-0.157-0.02110.48110.5082-0.4668-0.0298-0.2448-0.0981-0.0184-0.07650.0887-0.0405-12.4564-44.5383-29.0082
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|516 - 662}A516 - 662
2X-RAY DIFFRACTION2{A|663 - 794}A663 - 794

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