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- PDB-5ap3: Naturally Occurring Mutations in the MPS1 Gene Predispose Cells t... -

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Basic information

Entry
Database: PDB / ID: 5ap3
TitleNaturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance.
ComponentsDUAL SPECIFICITY PROTEIN KINASE TTK
KeywordsTRANSFERASE / MPS1 / PROTEIN KINASE / MITOSIS / DRUG RESISTANCE
Function / homology
Function and homology information


protein localization to meiotic spindle midzone / meiotic spindle assembly checkpoint signaling / repair of mitotic kinetochore microtubule attachment defect / kinetochore binding / female meiosis chromosome segregation / protein localization to kinetochore / dual-specificity kinase / spindle organization / mitotic spindle assembly checkpoint signaling / positive regulation of SMAD protein signal transduction ...protein localization to meiotic spindle midzone / meiotic spindle assembly checkpoint signaling / repair of mitotic kinetochore microtubule attachment defect / kinetochore binding / female meiosis chromosome segregation / protein localization to kinetochore / dual-specificity kinase / spindle organization / mitotic spindle assembly checkpoint signaling / positive regulation of SMAD protein signal transduction / 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 / nucleus / membrane / cytoplasm
Similarity search - Function
Protein kinase Mps1 family / Tetratricopeptide-like helical domain superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-7PE / Chem-AU5 / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsGurden, M.D. / Westwood, I.M. / Faisal, A. / Naud, S. / Cheung, K.J. / McAndrew, C. / Wood, A. / Schmitt, J. / Boxall, K. / Mak, G. ...Gurden, M.D. / Westwood, I.M. / Faisal, A. / Naud, S. / Cheung, K.J. / McAndrew, C. / Wood, A. / Schmitt, J. / Boxall, K. / Mak, G. / Workman, P. / Burke, R. / Hoelder, S. / Blagg, J. / van Montfort, R.L.M. / Linardopoulos, S.
CitationJournal: Cancer Res. / Year: 2015
Title: Naturally Occurring Mutations in the Mps1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance.
Authors: Gurden, M.D. / Westwood, I.M. / Faisal, A. / Naud, S. / Cheung, K.J. / Mcandrew, C. / Wood, A. / Schmitt, J. / Boxall, K. / Mak, G. / Workman, P. / Burke, R. / Hoelder, S. / Blagg, J. / Van ...Authors: Gurden, M.D. / Westwood, I.M. / Faisal, A. / Naud, S. / Cheung, K.J. / Mcandrew, C. / Wood, A. / Schmitt, J. / Boxall, K. / Mak, G. / Workman, P. / Burke, R. / Hoelder, S. / Blagg, J. / Van Montfort, R.L.M. / Linardopoulos, S.
History
DepositionSep 14, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 23, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.2Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)38,12410
Polymers36,1651
Non-polymers1,9589
Water37821
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)70.730, 111.250, 112.010
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 / MONOPOLAR SPINDLE KINASE 1


Mass: 36165.211 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, UNP RESIDUES 519-808 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): AI / References: UniProt: P33981, dual-specificity kinase

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Non-polymers , 5 types, 30 molecules

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


Mass: 310.384 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H30O7
#3: Chemical ChemComp-AU5 / 9-CYCLOPENTYL-2-[[2-METHOXY-4-[(1-METHYLPIPERIDIN-4-YL)OXY]-PHENYL]AMINO]-7-METHYL-7,9-DIHYDRO-8H-PURIN-8-ONE


Mass: 452.549 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H32N6O3
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY
Nonpolymer details9-CYCLOPENTYL-2-[[2-METHOXY-4-[(1-METHYLPIPERIDIN-4-YL)OXY]-PHENYL]A
Sequence detailsTHE SEQUENCE INCLUDING HEXAHISTIDINE TAG IS AS DESCRIBED IN NAT. CHEM. BIOL. 2010, 6, 259-368 WITH ...THE SEQUENCE INCLUDING HEXAHISTIDINE TAG IS AS DESCRIBED IN NAT. CHEM. BIOL. 2010, 6, 259-368 WITH AN ADDITIONAL MUTATION S611G

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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: 3.05 Å3/Da / Density % sol: 59.62 % / Description: NONE
Crystal growpH: 7.5 / Details: 38% (V/V) PEG300, pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9173
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: May 23, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9173 Å / Relative weight: 1
ReflectionResolution: 2.7→59.69 Å / Num. obs: 12109 / % possible obs: 97.4 % / Observed criterion σ(I): 0 / Redundancy: 3.9 % / Biso Wilson estimate: 93.98 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 9.3
Reflection shellResolution: 2.7→2.83 Å / Redundancy: 4 % / Mean I/σ(I) obs: 1 / % possible all: 99.4

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4C4J

4c4j


Resolution: 2.7→59.69 Å / Cor.coef. Fo:Fc: 0.9461 / Cor.coef. Fo:Fc free: 0.9166 / SU R Cruickshank DPI: 0.397 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.395 / SU Rfree Blow DPI: 0.266 / SU Rfree Cruickshank DPI: 0.269
RfactorNum. reflection% reflectionSelection details
Rfree0.2362 573 4.73 %RANDOM
Rwork0.1899 ---
obs0.192 12106 96.95 %-
Displacement parametersBiso mean: 88.73 Å2
Baniso -1Baniso -2Baniso -3
1-9.591 Å20 Å20 Å2
2---3.4224 Å20 Å2
3----6.1686 Å2
Refine analyzeLuzzati coordinate error obs: 0.411 Å
Refinement stepCycle: LAST / Resolution: 2.7→59.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2003 0 104 21 2128
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092148HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.072894HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d754SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes55HARMONIC2
X-RAY DIFFRACTIONt_gen_planes315HARMONIC5
X-RAY DIFFRACTIONt_it2148HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.32
X-RAY DIFFRACTIONt_other_torsion20.61
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion277SEMIHARMONIC5
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_contact2430SEMIHARMONIC4
LS refinement shellResolution: 2.7→2.96 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2686 140 4.86 %
Rwork0.2396 2738 -
all0.241 2878 -
obs--96.95 %
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)
17.6614-2.0159-1.40373.3767-0.68491.5125-0.02610.36280.5442-0.02160.0940.0033-0.1383-0.0879-0.0679-0.2744-0.0388-0.0045-0.26370.08850.0699-1.17338.3884132.859
22.34350.1881-0.342.767-0.52426.08590.01620.5442-0.1745-0.3423-0.267-0.16150.41730.2460.2509-0.3040.0920.0339-0.16650.03740.122213.425623.3034122.519
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|516 - 662}
2X-RAY DIFFRACTION2{A|663 - 794}

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