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- PDB-6h3k: Introduction of a methyl group curbs metabolism of pyrido[3,4-d]p... -

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Basic information

Entry
Database: PDB / ID: 6h3k
TitleIntroduction of a methyl group curbs metabolism of pyrido[3,4-d]pyrimidine MPS1 inhibitors and enables the discovery of the Phase 1 clinical candidate BOS172722.
ComponentsDual specificity protein kinase TTK
KeywordsTRANSFERASE / Kinase / Spindle assembly checkpoint / mitosis
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 / kinetochore / spindle / 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-7PE / Chem-FMW / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.48 Å
AuthorsWoodward, H.L. / Hoelder, S.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
United Kingdom
CitationJournal: J. Med. Chem. / Year: 2018
Title: Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4- d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4- ...Title: Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4- d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4-methyl-4 H-1,2,4-triazol-3-yl)phenyl)-6-methyl- N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine (BOS172722).
Authors: Woodward, H.L. / Innocenti, P. / Cheung, K.J. / Hayes, A. / Roberts, J. / Henley, A.T. / Faisal, A. / Mak, G.W. / Box, G. / Westwood, I.M. / Cronin, N. / Carter, M. / Valenti, M. / De Haven ...Authors: Woodward, H.L. / Innocenti, P. / Cheung, K.J. / Hayes, A. / Roberts, J. / Henley, A.T. / Faisal, A. / Mak, G.W. / Box, G. / Westwood, I.M. / Cronin, N. / Carter, M. / Valenti, M. / De Haven Brandon, A. / O'Fee, L. / Saville, H. / Schmitt, J. / Burke, R. / Broccatelli, F. / van Montfort, R.L.M. / Raynaud, F.I. / Eccles, S.A. / Linardopoulos, S. / Blagg, J. / Hoelder, S.
History
DepositionJul 19, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 19, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 10, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)33,0023
Polymers32,2451
Non-polymers7572
Water66737
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area290 Å2
ΔGint-7 kcal/mol
Surface area13550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.624, 107.644, 114.683
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-935-

HOH

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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
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-FMW / ~{N}8-(2,2-dimethylpropyl)-~{N}2-[2-ethoxy-4-(4-methyl-1,2,4-triazol-3-yl)phenyl]-6-methyl-pyrido[3,4-d]pyrimidine-2,8-diamine


Mass: 446.548 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H30N8O
#3: Chemical ChemComp-7PE / 2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL / POLYETHYLENE GLYCOL FRAGMENT / Polyethylene glycol


Mass: 310.384 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H30O7
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 37 / 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: 3.43 Å3/Da / Density % sol: 64.12 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M Bis-Tris propane; 0.1 M MgCl2 0.1 M Sodium formate 18-26% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9282 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Aug 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9282 Å / Relative weight: 1
ReflectionResolution: 2.67→60.52 Å / Num. obs: 12793 / % possible obs: 99.7 % / Redundancy: 6.5 % / Biso Wilson estimate: 79.3 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.092 / Rpim(I) all: 0.039 / Rrim(I) all: 0.101 / Net I/σ(I): 11.7 / Num. measured all: 83046
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.67-2.746.51.7860949410.6220.7551.936199.7
11.94-60.525.50.0399271700.9980.0170.04338.198.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å41.33 Å
Translation3.5 Å41.33 Å

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Processing

Software
NameVersionClassificationNB
BUSTERrefinement
XDSdata reduction
Aimlessdata scaling
PHASER2.5.7phasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.48→41.33 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.893 / SU R Cruickshank DPI: 0.268 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.266 / SU Rfree Blow DPI: 0.204 / SU Rfree Cruickshank DPI: 0.206
RfactorNum. reflection% reflectionSelection details
Rfree0.231 798 4.98 %RANDOM
Rwork0.208 ---
obs0.209 16023 99.6 %-
Displacement parametersBiso max: 190.04 Å2 / Biso mean: 103.23 Å2 / Biso min: 62.29 Å2
Baniso -1Baniso -2Baniso -3
1-27.1364 Å20 Å20 Å2
2---14.5163 Å20 Å2
3----12.6201 Å2
Refine analyzeLuzzati coordinate error obs: 0.45 Å
Refinement stepCycle: final / Resolution: 2.48→41.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2003 0 40 37 2080
Biso mean--99.36 88.74 -
Num. residues----257
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d707SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes376HARMONIC5
X-RAY DIFFRACTIONt_it2089HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion278SEMIHARMONIC5
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_contact2132SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2089HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg2840HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion2.14
X-RAY DIFFRACTIONt_other_torsion20.73
LS refinement shellResolution: 2.48→2.5 Å / Rfactor Rfree error: 0 / Total num. of bins used: 39
RfactorNum. reflection% reflection
Rfree0.2871 19 4.62 %
Rwork0.3079 392 -
all0.3069 411 -
obs--99.27 %
Refinement TLS params.Method: refined / Origin x: -4.5872 Å / Origin y: -37.5148 Å / Origin z: -22.0688 Å
111213212223313233
T-0.2766 Å2-0.0228 Å20.0639 Å2--0.0845 Å20.2537 Å2---0.1028 Å2
L7.351 °20.6976 °21.1305 °2-2.2797 °20.0754 °2--3.0268 °2
S0.0824 Å °-0.7101 Å °-1.0018 Å °0.0638 Å °-0.0309 Å °0.2722 Å °0.0842 Å °-0.0828 Å °-0.0515 Å °
Refinement TLS groupSelection details: { A|* }

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