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- PDB-8bju: HUMAN WEE1 KINASE IN COMPLEX WITH INHIBITOR 1-[6-(1-Hydroxy-1-met... -

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Basic information

Entry
Database: PDB / ID: 8bju
TitleHUMAN WEE1 KINASE IN COMPLEX WITH INHIBITOR 1-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-2-yl]-2-(2-methoxy-phenyl)-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one
ComponentsWee1-like protein kinase
KeywordsTRANSFERASE / WEE1 / KINASE / PROTEIN-INHIBITOR COMPLEX
Function / homology
Function and homology information


G2/M DNA replication checkpoint / negative regulation of G2/M transition of mitotic cell cycle / Polo-like kinase mediated events / negative regulation of G1/S transition of mitotic cell cycle / establishment of cell polarity / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Cyclin E associated events during G1/S transition / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / neuron projection morphogenesis ...G2/M DNA replication checkpoint / negative regulation of G2/M transition of mitotic cell cycle / Polo-like kinase mediated events / negative regulation of G1/S transition of mitotic cell cycle / establishment of cell polarity / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Cyclin E associated events during G1/S transition / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / neuron projection morphogenesis / positive regulation of DNA replication / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / microtubule cytoskeleton organization / G2/M transition of mitotic cell cycle / Factors involved in megakaryocyte development and platelet production / protein tyrosine kinase activity / cell division / nucleolus / magnesium ion binding / nucleoplasm / ATP binding / nucleus / cytoplasm
Similarity search - Function
Wee1-like protein kinase / : / 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
Chem-QT9 / Wee1-like protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.53 Å
AuthorsMusil, D. / Lan, R.
Funding support Germany, 1items
OrganizationGrant numberCountry
Not funded Germany
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Selective Wee1 Inhibitors Led to Antitumor Activity In Vitro and Correlated with Myelosuppression.
Authors: Guler, S. / DiPoto, M.C. / Crespo, A. / Caldwell, R. / Doerfel, B. / Grossmann, N. / Ho, K. / Huck, B. / Jones, C.C. / Lan, R. / Musil, D. / Potnick, J. / Schilke, H. / Sherer, B. / Simon, S. ...Authors: Guler, S. / DiPoto, M.C. / Crespo, A. / Caldwell, R. / Doerfel, B. / Grossmann, N. / Ho, K. / Huck, B. / Jones, C.C. / Lan, R. / Musil, D. / Potnick, J. / Schilke, H. / Sherer, B. / Simon, S. / Sirrenberg, C. / Zhang, Z. / Liu-Bujalski, L.
History
DepositionNov 6, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 31, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: 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: Wee1-like protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7352
Polymers32,1691
Non-polymers5671
Water3,711206
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13410 Å2
Unit cell
Length a, b, c (Å)46.622, 50.577, 117.570
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Wee1-like protein kinase / WEE1hu / Wee1A kinase


Mass: 32168.641 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WEE1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P30291, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-QT9 / 2-(2-methoxyphenyl)-6-[[4-(4-methylpiperazin-1-yl)phenyl]amino]-1-[6-(2-oxidanylpropan-2-yl)pyridin-2-yl]pyrazolo[3,4-d]pyrimidin-3-one


Mass: 566.653 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H34N8O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 206 / 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: 2.15 Å3/Da / Density % sol: 42.91 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 4.75 / Details: 6.0 % w/v PEG6000, 0.10M MES pH 4.75

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99989 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 13, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99989 Å / Relative weight: 1
ReflectionResolution: 1.53→117.57 Å / Num. obs: 36028 / % possible obs: 84.1 % / Redundancy: 8.1 % / CC1/2: 0.999 / Rpim(I) all: 0.022 / Rrim(I) all: 0.063 / Net I/σ(I): 17.7
Reflection shellResolution: 1.53→1.616 Å / Redundancy: 7.6 % / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1801 / CC1/2: 0.637 / Rpim(I) all: 0.46

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Processing

Software
NameClassification
BUSTERrefinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2io6

2io6


Resolution: 1.53→21.25 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.931 / SU R Cruickshank DPI: 0.107 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.112 / SU Rfree Blow DPI: 0.112 / SU Rfree Cruickshank DPI: 0.109
RfactorNum. reflection% reflectionSelection details
Rfree0.263 1675 4.66 %RANDOM
Rwork0.2206 ---
obs0.2227 35957 84.1 %-
Displacement parametersBiso mean: 34.13 Å2
Baniso -1Baniso -2Baniso -3
1--0.1505 Å20 Å20 Å2
2--0.5759 Å20 Å2
3----0.4254 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: 1 / Resolution: 1.53→21.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2105 0 42 206 2353
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0112212HARMONIC2
X-RAY DIFFRACTIONt_angle_deg12994HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d787SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes374HARMONIC5
X-RAY DIFFRACTIONt_it2212HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.43
X-RAY DIFFRACTIONt_other_torsion15.56
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion274SEMIHARMONIC5
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_contact2159SEMIHARMONIC4
LS refinement shellResolution: 1.53→1.58 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3589 -4.03 %
Rwork0.3171 691 -
all0.3187 720 -
Refinement TLS params.Method: refined / Origin x: -12.3138 Å / Origin y: -1.2849 Å / Origin z: 14.005 Å
111213212223313233
T0.0296 Å20.1434 Å20.0529 Å2-0.0727 Å20.0551 Å2---0.0563 Å2
L0.7494 °20.0954 °20.3547 °2-1.3867 °2-0.1685 °2--0.3114 °2
S0.0104 Å °-0.0198 Å °0.0346 Å °-0.1991 Å °-0.1752 Å °-0.1105 Å °0.0349 Å °-0.0202 Å °0.1648 Å °
Refinement TLS groupSelection details: { A|* }

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