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- PDB-7avq: Crystal structure of haspin in complex with disubstituted imidazo... -

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Basic information

Entry
Database: PDB / ID: 7avq
TitleCrystal structure of haspin in complex with disubstituted imidazo[1,2- b]pyridazine inhibitor (compound 12)
ComponentsSerine/threonine-protein kinase haspin
KeywordsTRANSFERASE / kinase / haspin / GSG2 / inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


histone H3T3 kinase activity / protein localization to chromosome, centromeric region / mitotic sister chromatid cohesion / mitotic spindle assembly checkpoint signaling / spindle / chromosome / mitotic cell cycle / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction ...histone H3T3 kinase activity / protein localization to chromosome, centromeric region / mitotic sister chromatid cohesion / mitotic spindle assembly checkpoint signaling / spindle / chromosome / mitotic cell cycle / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / centrosome / nucleoplasm / ATP binding / nucleus / cytoplasm
Similarity search - Function
Serine/threonine-protein kinase haspin, C-terminal / Domain of unknown function / Haspin like 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-S1Z / Serine/threonine-protein kinase haspin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsChaikuad, A. / Bonnet, P. / Routier, S. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J Enzyme Inhib Med Chem / Year: 2020
Title: Design of new disubstituted imidazo[1,2- b ]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation.
Authors: Elie, J. / Feizbakhsh, O. / Desban, N. / Josselin, B. / Baratte, B. / Bescond, A. / Duez, J. / Fant, X. / Bach, S. / Marie, D. / Place, M. / Ben Salah, S. / Chartier, A. / Berteina-Raboin, S. ...Authors: Elie, J. / Feizbakhsh, O. / Desban, N. / Josselin, B. / Baratte, B. / Bescond, A. / Duez, J. / Fant, X. / Bach, S. / Marie, D. / Place, M. / Ben Salah, S. / Chartier, A. / Berteina-Raboin, S. / Chaikuad, A. / Knapp, S. / Carles, F. / Bonnet, P. / Buron, F. / Routier, S. / Ruchaud, S.
History
DepositionNov 5, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 8, 2021Group: Database references / Structure summary / Category: audit_author / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Jan 31, 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: Serine/threonine-protein kinase haspin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,3596
Polymers40,7111
Non-polymers6485
Water5,296294
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area950 Å2
ΔGint-23 kcal/mol
Surface area15140 Å2
Unit cell
Length a, b, c (Å)70.349, 78.009, 86.150
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Serine/threonine-protein kinase haspin / Germ cell-specific gene 2 protein / H-haspin / Haploid germ cell-specific nuclear protein kinase


Mass: 40711.484 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HASPIN, GSG2 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2
References: UniProt: Q8TF76, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 299 molecules

#2: Chemical ChemComp-S1Z / (2~{R})-2-[[3-(2~{H}-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl]amino]butan-1-ol


Mass: 322.364 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H18N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL / 2-Methyl-2,4-pentanediol


Mass: 118.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 294 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.9 Å3/Da / Density % sol: 57.63 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / Details: 63% MPD and 0.1 M SPG, pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97626 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97626 Å / Relative weight: 1
ReflectionResolution: 1.65→57.83 Å / Num. obs: 56638 / % possible obs: 98.3 % / Redundancy: 5.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.031 / Rrim(I) all: 0.074 / Net I/av σ(I): 4.8 / Net I/σ(I): 11.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible allRsym value
1.65-1.745.10.7762.280800.7160.370.86297.1
1.74-1.845.30.4571.676690.2150.50697.80.457
1.84-1.975.30.2562.872430.120.284980.256
1.97-2.135.40.1464.767930.0680.16298.50.146
2.13-2.335.30.1016.763030.0480.11298.50.101
2.33-2.615.30.0768.356980.0360.08598.50.076
2.61-3.015.40.0629.451090.0290.06999.50.062
3.01-3.695.40.04911.443290.0230.055990.049
3.69-5.225.20.04712.734250.0220.05299.40.047
5.22-54.4950.056.419890.0240.05599.50.05

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Processing

Software
NameVersionClassification
SCALA3.3.22data scaling
REFMAC5.8.0131refinement
PDB_EXTRACT3.27data extraction
iMOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4OUC

4ouc


Resolution: 1.65→57.83 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.969 / SU B: 3.336 / SU ML: 0.056 / SU R Cruickshank DPI: 0.0725 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.073 / ESU R Free: 0.072 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1794 2837 5 %RANDOM
Rwork0.1593 ---
obs0.1603 53758 98.05 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 81.47 Å2 / Biso mean: 32.098 Å2 / Biso min: 17.1 Å2
Baniso -1Baniso -2Baniso -3
1-1.49 Å20 Å20 Å2
2--0.21 Å2-0 Å2
3----1.69 Å2
Refinement stepCycle: final / Resolution: 1.65→57.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2627 0 45 294 2966
Biso mean--32.47 41.22 -
Num. residues----328
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192803
X-RAY DIFFRACTIONr_bond_other_d0.0020.022698
X-RAY DIFFRACTIONr_angle_refined_deg1.611.9623804
X-RAY DIFFRACTIONr_angle_other_deg0.91736240
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2925351
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.78124.444126
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.8315511
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8221513
X-RAY DIFFRACTIONr_chiral_restr0.1010.2425
X-RAY DIFFRACTIONr_gen_planes_refined0.010.023256
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02647
LS refinement shellResolution: 1.65→1.693 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.282 215 -
Rwork0.266 3847 -
all-4062 -
obs--96.03 %
Refinement TLS params.Method: refined / Origin x: 80.5891 Å / Origin y: 72.0721 Å / Origin z: 35.1926 Å
111213212223313233
T0.0145 Å2-0.0028 Å2-0.002 Å2-0.0371 Å20.0204 Å2--0.014 Å2
L1.0084 °20.4668 °20.1761 °2-2.1837 °20.9572 °2--1.7709 °2
S-0.0108 Å °-0.1154 Å °-0.0432 Å °0.1253 Å °-0.0229 Å °-0.0343 Å °0.1301 Å °-0.0031 Å °0.0336 Å °

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