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- PDB-5mrb: Crystal structure of human Mps1 (TTK) in complex with Cpd-5 -

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Basic information

Entry
Database: PDB / ID: 5mrb
TitleCrystal structure of human Mps1 (TTK) in complex with Cpd-5
ComponentsDual specificity protein kinase TTK
KeywordsTRANSFERASE / Mps1 / TTK / kinase / inhibitor / Cpd-5 / Compound 5
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-C5N / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2 Å
AuthorsHiruma, Y. / Joosten, R.P. / Perrakis, A.
Funding support Netherlands, 3items
OrganizationGrant numberCountry
NWO722.015.008 Netherlands
NWO723.013.003 Netherlands
KWF2012-5427 Netherlands
CitationJournal: J. Biol. Chem. / Year: 2017
Title: Understanding inhibitor resistance in Mps1 kinase through novel biophysical assays and structures.
Authors: Hiruma, Y. / Koch, A. / Hazraty, N. / Tsakou, F. / Medema, R.H. / Joosten, R.P. / Perrakis, A.
History
DepositionDec 22, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 26, 2017Provider: repository / Type: Initial release
Revision 1.1Aug 2, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Aug 9, 2017Group: Data collection / Category: diffrn_source
Item: _diffrn_source.pdbx_synchrotron_beamline / _diffrn_source.type
Revision 1.3Aug 23, 2017Group: Data collection / Category: diffrn_source
Item: _diffrn_source.pdbx_synchrotron_beamline / _diffrn_source.type
Revision 1.4Sep 13, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.5Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dual specificity protein kinase TTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,53615
Polymers36,1751
Non-polymers1,36114
Water1,26170
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2350 Å2
ΔGint25 kcal/mol
Surface area14010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.582, 111.419, 115.025
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: 36175.289 Da / Num. of mol.: 1 / Mutation: C604Y
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTK, MPS1, MPS1L1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P33981, dual-specificity kinase
#2: Chemical ChemComp-C5N / ~{N}-(2,6-diethylphenyl)-8-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide


Mass: 580.723 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H40N8O2
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 70 / 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: 3.13 Å3/Da / Density % sol: 60.65 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.8
Details: Protein solution: 200 uM (7.2 mg/mL) Mps1, 250 uM Cpd-5. Reservoir solution: 15.5% (w/v) PEG 350 MME, 10 mM MgCl2, and 100 mM Tris/HCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.96771 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Apr 16, 2016
RadiationMonochromator: Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96771 Å / Relative weight: 1
ReflectionResolution: 2.2→41.39 Å / Num. obs: 23225 / % possible obs: 99.3 % / Redundancy: 4.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.046 / Net I/σ(I): 18.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Diffraction-ID% possible all
2.2-2.274.80.8680.702199.8
9.07-41.3940.0210.999195.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation6.24 Å41.39 Å
Translation6.24 Å41.39 Å

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Processing

Software
NameVersionClassification
Aimless0.5.25data scaling
PHASER2.6.1phasing
REFMACrefmac_5.8.0155refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3HMN

3hmn


Resolution: 2.2→41.39 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.95 / Matrix type: sparse / SU B: 9.558 / SU ML: 0.116 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.166 / ESU R Free: 0.158
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2159 1214 5.2 %RANDOM
Rwork0.1732 ---
obs0.1753 22011 99.12 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.1 Å
Displacement parametersBiso max: 157.01 Å2 / Biso mean: 61.265 Å2 / Biso min: 35.9 Å2
Baniso -1Baniso -2Baniso -3
1--0.81 Å2-0 Å20 Å2
2---2.12 Å20 Å2
3---2.94 Å2
Refinement stepCycle: final / Resolution: 2.2→41.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2164 0 92 70 2326
Biso mean--65.63 63.38 -
Num. residues----264
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0192297
X-RAY DIFFRACTIONr_bond_other_d0.0020.022234
X-RAY DIFFRACTIONr_angle_refined_deg1.3661.9673085
X-RAY DIFFRACTIONr_angle_other_deg0.8912.9755152
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8455261
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.8725.481104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.74615415
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.582156
X-RAY DIFFRACTIONr_chiral_restr0.0870.2328
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212502
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02499
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)WRfactor Rwork
2.2-2.2570.3041070.271597170999.7070.244
2.257-2.3190.316900.2511551164799.6360.222
2.319-2.3860.242690.2221539161499.6280.19
2.386-2.4590.224680.1961516159399.4350.168
2.459-2.540.259790.1961435152399.4090.166
2.54-2.6290.236680.1911395147399.3210.159
2.629-2.7280.201980.1711333144099.3750.145
2.728-2.8390.156790.1711286137399.4170.14
2.839-2.9660.252730.1631225130799.3110.137
2.966-3.110.217510.1711216127899.1390.148
3.11-3.2780.16660.1691118122196.970.151
3.278-3.4770.226550.1671047114096.6670.155
3.477-3.7160.252600.171002107498.8830.162
3.716-4.0130.18510.14896210131000.145
4.013-4.3950.18380.1499019391000.154
4.395-4.9120.174450.1480084699.8820.147
4.912-5.6680.23370.16870974999.5990.175
5.668-6.9330.257420.20660865499.3880.215
6.933-9.7690.269300.15248551899.4210.169
9.769-80.030.16180.23528631593.3330.268
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)
12.6921-2.1895-0.8916.58970.49220.4758-0.0783-0.27250.21120.16270.2122-0.56920.00490.2175-0.13390.06460.0107-0.03580.13-0.0790.135810.3785-10.4612-22.0152
24.3160.8437-0.69612.4740.59661.63550.0275-0.10320.05220.0126-0.0436-0.0471-0.0207-0.00960.01610.04230.0262-0.03350.0212-0.02320.0301-3.2399-19.3581-21.1932
32.905-0.17750.45912.86960.22654.53960.0457-0.7384-0.39710.4117-0.14530.08690.26-0.12450.09960.1118-0.07730.04420.24350.04970.1254-14.7395-31.1765-9.9632
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A514 - 569
2X-RAY DIFFRACTION2A570 - 677
3X-RAY DIFFRACTION3A683 - 795

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