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- PDB-7o2v: AURORA KINASE A IN COMPLEX WITH THE AUR-A/PDK1 INHIBITOR VI8 -

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Basic information

Entry
Database: PDB / ID: 7o2v
TitleAURORA KINASE A IN COMPLEX WITH THE AUR-A/PDK1 INHIBITOR VI8
ComponentsAurora kinase A
KeywordsTRANSFERASE / SERINE/THREONINE / KINASE / AURORA / INHIBITOR / CRYSTAL / COMPLEX / CANCER / TUMOR / DUAL / ATP-BINDING / STRUCTURE-BASED / DRUG DESIGN / SBDD
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 / spindle pole centrosome / chromosome passenger complex / positive regulation of oocyte maturation / pronucleus / mitotic centrosome separation ...Interaction between PHLDA1 and AURKA / regulation of centrosome cycle / axon hillock / spindle assembly involved in female meiosis I / cilium disassembly / spindle pole centrosome / chromosome passenger complex / positive regulation of oocyte maturation / pronucleus / mitotic centrosome separation / germinal vesicle / meiotic spindle / 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 / negative regulation of protein binding / centriole / protein serine/threonine/tyrosine kinase activity / positive regulation of mitotic nuclear division / positive regulation of mitotic cell cycle / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / molecular function activator activity / AURKA Activation by TPX2 / regulation of cytokinesis / liver regeneration / regulation of signal transduction by p53 class mediator / mitotic spindle organization / 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 / kinetochore / response to wounding / spindle / spindle pole / G2/M transition of mitotic cell cycle / mitotic spindle / Regulation of PLK1 Activity at G2/M Transition / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / mitotic cell cycle / peptidyl-serine phosphorylation / microtubule cytoskeleton / midbody / protein autophosphorylation / basolateral plasma membrane / Regulation of TP53 Activity through Phosphorylation / microtubule / proteasome-mediated ubiquitin-dependent protein catabolic process / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / postsynaptic density / ciliary basal body / protein phosphorylation / protein heterodimerization activity / cell division / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / centrosome / ubiquitin protein ligase binding / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / glutamatergic synapse / 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
Chem-V0K / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsGarau, G.
Citation
Journal: Eur.J.Med.Chem. / Year: 2021
Title: Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile.
Authors: Sestito, S. / Bacci, A. / Chiarugi, S. / Runfola, M. / Gado, F. / Margheritis, E. / Gul, S. / Riveiro, M.E. / Vazquez, R. / Huguet, S. / Manera, C. / Rezai, K. / Garau, G. / Rapposelli, S.
#1: Journal: ACS Chem. Neurosci. / Year: 2016
Title: Dual Inhibition of PDK1 and Aurora Kinase A: An Effective Strategy to Induce Differentiation and Apoptosis of Human Glioblastoma Multiforme Stem Cells
Authors: Simona Daniele, S. / Sestito, S. / Pietrobono, D. / Giacomelli, C. / Chiellini, G. / Di Maio, D. / Marinelli, L. / Novellino, E. / Martini, C. / Rapposelli, S.
History
DepositionMar 31, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 20, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 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: Aurora kinase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4952
Polymers34,8751
Non-polymers6211
Water34219
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.129, 82.129, 166.292
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Space group name HallP612(x,y,z+5/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+2/3
#8: -x,-y,z+1/2
#9: y,x,-z+1/3
#10: -y,-x,-z+5/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+1/6
Components on special symmetry positions
IDModelComponents
11A-619-

HOH

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Components

#1: Protein Aurora kinase A / Aurora 2 / Aurora/IPL1-related kinase 1 / ARK-1 / Aurora-related kinase 1 / hARK1 / Breast tumor- ...Aurora 2 / Aurora/IPL1-related kinase 1 / ARK-1 / Aurora-related kinase 1 / hARK1 / Breast tumor-amplified kinase / Serine/threonine-protein kinase 15 / Serine/threonine-protein kinase 6 / Serine/threonine-protein kinase aurora-A


Mass: 34874.773 Da / Num. of mol.: 1
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
Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-V0K / 1-[[3,4-bis(fluoranyl)phenyl]methyl]-~{N}-[(1~{R})-2-[[(3~{E})-3-(1~{H}-imidazol-5-ylmethylidene)-2-oxidanylidene-1~{H}-indol-5-yl]amino]-2-oxidanylidene-1-phenyl-ethyl]-6-methyl-2-oxidanylidene-pyridine-3-carboxamide


Mass: 620.605 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H26F2N6O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 19 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.32 Å3/Da / Density % sol: 47.01 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.2 M HEPES pH 7.5, 0.2 M (NH4)2SO4, 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ELETTRA / Beamline: 11.2C / Wavelength: 0.9785 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9785 Å / Relative weight: 1
ReflectionResolution: 3.1→71.13 Å / Num. obs: 6602 / % possible obs: 100 % / Redundancy: 31 % / Biso Wilson estimate: 95.77 Å2 / CC1/2: 0.81 / Net I/σ(I): 4.7
Reflection shellResolution: 3.1→3.25 Å / Num. unique obs: 1149 / CC1/2: 0.3

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Processing

Software
NameVersionClassification
MxCuBE1.19.2_4158data collection
PHENIX1.19.2_4158refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3FDN

3fdn


Resolution: 3.1→30.13 Å / SU ML: 0.5979 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 36.5043
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3286 335 5.38 %
Rwork0.2721 5889 -
obs0.275 6224 95.55 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 112.53 Å2
Refinement stepCycle: LAST / Resolution: 3.1→30.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2174 0 46 19 2239
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00662277
X-RAY DIFFRACTIONf_angle_d1.23793075
X-RAY DIFFRACTIONf_chiral_restr0.0612321
X-RAY DIFFRACTIONf_plane_restr0.0069391
X-RAY DIFFRACTIONf_dihedral_angle_d11.3807297
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1-3.310.41231610.37372717X-RAY DIFFRACTION91.05
3.9-30.130.30121740.2393172X-RAY DIFFRACTION99.79
Refinement TLS params.Method: refined / Origin x: -15.6484284122 Å / Origin y: -31.9693979447 Å / Origin z: 8.4320170281 Å
111213212223313233
T0.919360893565 Å20.243372289575 Å20.115772686642 Å2-0.793782930915 Å2-0.0752708221807 Å2--0.643620367766 Å2
L8.71966889104 °22.10324045781 °21.80028044627 °2-4.9067251805 °2-0.102180856249 °2--1.51550672939 °2
S-0.532733488182 Å °-1.28624340727 Å °1.07016378814 Å °0.513242583889 Å °0.359857916693 Å °0.225248364439 Å °-0.279110448257 Å °-0.498845809595 Å °0.184149866584 Å °
Refinement TLS groupSelection details: all

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