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- PDB-8c1h: Aurora A kinase in complex with TPX2-inhibitor 8 -

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Basic information

Entry
Database: PDB / ID: 8c1h
TitleAurora A kinase in complex with TPX2-inhibitor 8
ComponentsAurora kinase A
KeywordsCELL CYCLE / protein-ligand complex / kinase / protein-protein interaction inhibitor
Function / homology
Function and homology information


Interaction between PHLDA1 and AURKA / regulation of centrosome cycle / axon hillock / spindle assembly involved in female meiosis I / cilium disassembly / positive regulation of oocyte maturation / spindle pole centrosome / histone H3S10 kinase activity / chromosome passenger complex / pronucleus ...Interaction between PHLDA1 and AURKA / regulation of centrosome cycle / axon hillock / spindle assembly involved in female meiosis I / cilium disassembly / positive regulation of oocyte maturation / spindle pole centrosome / histone H3S10 kinase activity / chromosome passenger complex / pronucleus / meiotic spindle / mitotic centrosome separation / germinal vesicle / protein localization to centrosome / anterior/posterior axis specification / centrosome localization / neuron projection extension / spindle organization / positive regulation of mitochondrial fission / mitotic spindle pole / SUMOylation of DNA replication proteins / spindle midzone / regulation of G2/M transition of mitotic cell cycle / centriole / protein serine/threonine/tyrosine kinase activity / positive regulation of mitotic cell cycle / positive regulation of mitotic nuclear division / AURKA Activation by TPX2 / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / mitotic spindle organization / ciliary basal body / regulation of cytokinesis / negative regulation of protein binding / regulation of signal transduction by p53 class mediator / molecular function activator activity / liver regeneration / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / regulation of protein stability / spindle microtubule / mitotic spindle / kinetochore / response to wounding / spindle / G2/M transition of mitotic cell cycle / microtubule cytoskeleton / Regulation of PLK1 Activity at G2/M Transition / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / mitotic cell cycle / midbody / basolateral plasma membrane / peptidyl-serine phosphorylation / proteasome-mediated ubiquitin-dependent protein catabolic process / Regulation of TP53 Activity through Phosphorylation / protein autophosphorylation / postsynaptic density / non-specific serine/threonine protein kinase / protein kinase activity / protein heterodimerization activity / cell division / protein phosphorylation / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / glutamatergic synapse / apoptotic process / ubiquitin protein ligase binding / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / nucleoplasm / ATP binding / nucleus / cytosol
Similarity search - Function
Aurora kinase A / Aurora 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
ACETATE ION / ADENOSINE-5'-DIPHOSPHATE / Chem-T3U / (1~{R},2~{R})-cyclohexane-1,2-dicarboxylic acid / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.233 Å
AuthorsFischer, G. / Rocaboy, M. / Blaszczyk, B. / Moschetti, T. / Wang, X. / Scott, D.E. / Coyne, A.G. / Dagostin, C. / Rooney, T. / Bayly, A. ...Fischer, G. / Rocaboy, M. / Blaszczyk, B. / Moschetti, T. / Wang, X. / Scott, D.E. / Coyne, A.G. / Dagostin, C. / Rooney, T. / Bayly, A. / Feng, J. / Asteian, A. / Alcaide-Lopez, A. / Stockwell, S. / Skidmore, J. / Venkitaraman, A.R. / Abell, C. / Blundell, T.L. / Hyvonen, M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust090340/Z/09/Z "101134/Z/13/Z United Kingdom
CitationJournal: To Be Published
Title: Selective inhibitors of the Aurora A-TPX2 protein-protein interaction exhibit in vivo efficacy as targeted anti-mitotic agent
Authors: Stockwell, S. / Scott, D. / Fischer, G. / Guarino Almeida, E. / Rooney, T. / Feng, J. / Moschetti, T. / Dagostin, C. / Alcaide-Lopez, A. / Rocaboy, M. / Srinivasan, R. / Asteian, A. / Alza, ...Authors: Stockwell, S. / Scott, D. / Fischer, G. / Guarino Almeida, E. / Rooney, T. / Feng, J. / Moschetti, T. / Dagostin, C. / Alcaide-Lopez, A. / Rocaboy, M. / Srinivasan, R. / Asteian, A. / Alza, E. / Blaszczyk, B. / Wang, X. / Rossmann, M. / Perrior, T. / Blundell, T.L. / Spring, D.R. / McKenzie, G. / Abell, C. / Skidmore, J. / Venkitaraman, A. / Hyvonen, M.
History
DepositionDec 20, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 10, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Aurora kinase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,65116
Polymers30,7501
Non-polymers1,90015
Water1,38777
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2580 Å2
ΔGint-80 kcal/mol
Surface area12470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.025, 81.025, 165.624
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-410-

SO4

21A-415-

CL

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Aurora kinase A / / Aurora 2 / Aurora/IPL1-related kinase 1 / ARK-1 / Aurora-related kinase 1 / Breast tumor-amplified ...Aurora 2 / Aurora/IPL1-related kinase 1 / ARK-1 / Aurora-related kinase 1 / Breast tumor-amplified kinase / Ipl1- and aurora-related kinase 1 / Serine/threonine-protein kinase 15 / Serine/threonine-protein kinase 6 / Serine/threonine-protein kinase Ayk1 / Serine/threonine-protein kinase aurora-A


Mass: 30750.326 Da / Num. of mol.: 1 / Fragment: Aurora A kinase / Mutation: C290A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: AURKA, AIK, AIRK1, ARK1, AURA, AYK1, BTAK, IAK1, STK15, STK6
Plasmid: pBAT4 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: O14965, non-specific serine/threonine protein kinase

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Non-polymers , 9 types, 92 molecules

#2: Chemical ChemComp-T3U / 4-(4-chloranyl-3-pyrazin-2-yloxy-phenyl)-~{N}-(dimethylsulfamoyl)-7-methyl-1~{H}-indole-6-carboxamide


Mass: 485.943 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20ClN5O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE / Adenosine diphosphate


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-T5L / (1~{R},2~{R})-cyclohexane-1,2-dicarboxylic acid


Mass: 172.178 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H12O4
#6: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#9: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: Cl
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 77 / 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: 2.55 Å3/Da / Density % sol: 51.8 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6.5
Details: 30% PEG5000 MME, 0.1M (NH4)2SO4, 0.1 M MES 6.5: soaking: 31.5% PEG5000 MME, 0.09M (NH4)2SO4, 0.09 M MES 6.5, 10% DMSO, 5 mM compound

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 25, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.233→64.61 Å / Num. obs: 15901 / % possible obs: 97.4 % / Redundancy: 11.6 % / Biso Wilson estimate: 53.45 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.089 / Rpim(I) all: 0.027 / Rrim(I) all: 0.093 / Net I/σ(I): 13.6 / Num. measured all: 184733
Reflection shellResolution: 2.233→2.241 Å / Redundancy: 12 % / Rmerge(I) obs: 0.983 / Num. unique obs: 152 / CC1/2: 0.858 / Rpim(I) all: 0.285 / Rrim(I) all: 1.025 / % possible all: 98.7

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
Aimlessdata scaling
PDB_EXTRACT3.23data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.233→64.61 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.896 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.277 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.298 / SU Rfree Blow DPI: 0.213 / SU Rfree Cruickshank DPI: 0.209
RfactorNum. reflection% reflectionSelection details
Rfree0.245 826 5.19 %RANDOM
Rwork0.211 ---
obs0.213 15900 96.9 %-
Displacement parametersBiso max: 234.4 Å2 / Biso mean: 63.41 Å2 / Biso min: 31.85 Å2
Baniso -1Baniso -2Baniso -3
1-15.0363 Å20 Å20 Å2
2--15.0363 Å20 Å2
3----30.0727 Å2
Refine analyzeLuzzati coordinate error obs: 0.39 Å
Refinement stepCycle: final / Resolution: 2.233→64.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2087 0 113 77 2277
Biso mean--77.31 63.43 -
Num. residues----258
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d776SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes48HARMONIC2
X-RAY DIFFRACTIONt_gen_planes366HARMONIC5
X-RAY DIFFRACTIONt_it2265HARMONIC20
X-RAY DIFFRACTIONt_nbd3SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion272SEMIHARMONIC5
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_contact2629SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2265HARMONIC20.011
X-RAY DIFFRACTIONt_angle_deg3080HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion3.28
X-RAY DIFFRACTIONt_other_torsion17.46
LS refinement shellResolution: 2.233→2.38 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.319 144 5.17 %
Rwork0.251 2643 -
obs--96.05 %

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