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- PDB-7lqd: Structure of Human MPS1 (TTK) covalently bound to RMS-07 inhibitor -

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Basic information

Entry
Database: PDB / ID: 7lqd
TitleStructure of Human MPS1 (TTK) covalently bound to RMS-07 inhibitor
ComponentsDual specificity protein kinase TTK or monopolar spindle 1 kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Protein kinase / inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


: / chromosome separation / protein serine/threonine kinase activity => GO:0004674 / 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 ...: / chromosome separation / protein serine/threonine kinase activity => GO:0004674 / 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 / transmembrane receptor protein tyrosine kinase activity / mitotic spindle organization / chromosome segregation / peptidyl-threonine phosphorylation / kinetochore / spindle / peptidyl-serine phosphorylation / protein tyrosine kinase activity / protein autophosphorylation / 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 / 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
Similarity search - Domain/homology
2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHOXYL / Chem-YB4 / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsSantiago, A.S. / dos Reis, C.V. / Serafim, R.A.M. / Massirer, K.B. / Arruda, P. / Edwards, A.M. / Counago, R.M. / Structural Genomics Consortium (SGC)
Funding support Brazil, 3items
OrganizationGrant numberCountry
Sao Paulo Research Foundation (FAPESP)2013/50724-5 Brazil
Brazilian National Council for Scientific and Technological Development (CNPq)465651/2014-3 Brazil
Sao Paulo Research Foundation (FAPESP)2014/50897-0 Brazil
CitationJournal: J.Med.Chem. / Year: 2022
Title: Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor.
Authors: M Serafim, R.A. / da Silva Santiago, A. / Schwalm, M.P. / Hu, Z. / Dos Reis, C.V. / Takarada, J.E. / Mezzomo, P. / Massirer, K.B. / Kudolo, M. / Gerstenecker, S. / Chaikuad, A. / Zender, L. ...Authors: M Serafim, R.A. / da Silva Santiago, A. / Schwalm, M.P. / Hu, Z. / Dos Reis, C.V. / Takarada, J.E. / Mezzomo, P. / Massirer, K.B. / Kudolo, M. / Gerstenecker, S. / Chaikuad, A. / Zender, L. / Knapp, S. / Laufer, S. / Counago, R.M. / Gehringer, M.
History
DepositionFeb 13, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 16, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dual specificity protein kinase TTK or monopolar spindle 1 kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3478
Polymers36,1151
Non-polymers1,2317
Water2,414134
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1590 Å2
ΔGint-7 kcal/mol
Surface area13570 Å2
2
A: Dual specificity protein kinase TTK or monopolar spindle 1 kinase
hetero molecules

A: Dual specificity protein kinase TTK or monopolar spindle 1 kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,69316
Polymers72,2312
Non-polymers2,46314
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_765-x+2,-y+1,z1
Buried area8290 Å2
ΔGint-48 kcal/mol
Surface area22030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.947, 103.137, 113.851
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 or monopolar spindle 1 kinase / Phosphotyrosine picked threonine-protein kinase / PYT


Mass: 36115.258 Da / Num. of mol.: 1 / Fragment: UNP residues 518-807
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTK, MPS1, MPS1L1 / Production host: Escherichia coli (E. coli) / References: UniProt: P33981-2, dual-specificity kinase
#2: Chemical ChemComp-YB4 / ~{N}-(2,6-diethylphenyl)-2-[[4-(4-methylpiperazin-1-yl)-2-(propanoylamino)phenyl]amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide


Mass: 606.760 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H42N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-TOE / 2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHOXYL


Mass: 164.200 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H16O4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 134 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.84 Å3/Da / Density % sol: 56.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.8
Details: 0.05 M magnesium chloride hexahydrate, 0.05 M sodium citrate tribasic, 0.1 M Bis-Tris propane, pH 7.8, 22.5% PEG Smear High

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 22, 2020
RadiationMonochromator: Cryogenically-cooled single crystal Si(220) side bounce
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.95→29.8 Å / Num. obs: 30369 / % possible obs: 99.9 % / Redundancy: 9.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.137 / Rpim(I) all: 0.047 / Rrim(I) all: 0.145 / Net I/σ(I): 8.8
Reflection shellResolution: 1.95→2 Å / Rmerge(I) obs: 1.685 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 2135 / CC1/2: 0.619 / Rpim(I) all: 0.79 / Rrim(I) all: 1.775

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5N84

5n84


Resolution: 1.95→20 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.946 / SU B: 8.93 / SU ML: 0.116 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.137 / ESU R Free: 0.14 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2462 1523 5 %RANDOM
Rwork0.1972 ---
obs0.1996 28817 99.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 84.14 Å2 / Biso mean: 40.873 Å2 / Biso min: 28.75 Å2
Baniso -1Baniso -2Baniso -3
1-0.84 Å2-0 Å20 Å2
2---2.63 Å20 Å2
3---1.79 Å2
Refinement stepCycle: final / Resolution: 1.95→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2137 0 86 135 2358
Biso mean--53.5 58.18 -
Num. residues----269
LS refinement shellResolution: 1.95→2 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.344 137 -
Rwork0.327 2072 -
all-2209 -
obs--99.73 %

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