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- PDB-3e5a: Crystal structure of Aurora A in complex with VX-680 and TPX2 -

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Basic information

Entry
Database: PDB / ID: 3e5a
TitleCrystal structure of Aurora A in complex with VX-680 and TPX2
Components
  • Serine/threonine-protein kinase 6
  • Targeting protein for Xklp2
KeywordsTRANSFERASE / AURORA A / SERINE/THREONINE-PROTEIN KINASE / COFACTOR / TPX2 / VX-680 / INHIBITOR / PHOSPHORYLATION / ATP-binding / Cell cycle / Nucleotide-binding / Phosphoprotein / Nucleus
Function / homology
Function and homology information


axon hillock / activation of protein kinase activity / negative regulation of microtubule depolymerization / Interaction between PHLDA1 and AURKA / regulation of centrosome cycle / cilium disassembly / spindle pole centrosome / importin-alpha family protein binding / mitotic centrosome separation / chromosome passenger complex ...axon hillock / activation of protein kinase activity / negative regulation of microtubule depolymerization / Interaction between PHLDA1 and AURKA / regulation of centrosome cycle / cilium disassembly / spindle pole centrosome / importin-alpha family protein binding / mitotic centrosome separation / chromosome passenger complex / regulation of G2/M transition of mitotic cell cycle / meiotic spindle organization / microtubule nucleation / spindle organization / positive regulation of mitochondrial fission / intercellular bridge / mitotic spindle pole / spindle midzone / SUMOylation of DNA replication proteins / mitotic spindle assembly / negative regulation of protein binding / liver regeneration / positive regulation of mitotic cell cycle / positive regulation of mitotic nuclear division / protein serine/threonine/tyrosine kinase activity / centriole / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / protein serine/threonine kinase activator activity / AURKA Activation by TPX2 / molecular function activator activity / regulation of signal transduction by p53 class mediator / mitotic spindle organization / regulation of mitotic spindle organization / regulation of cytokinesis / G2/M transition of mitotic cell cycle / regulation of protein stability / response to wounding / peptidyl-serine phosphorylation / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / mitotic spindle / kinetochore / spindle / microtubule cytoskeleton / mitotic cell cycle / Regulation of PLK1 Activity at G2/M Transition / protein autophosphorylation / microtubule / spindle pole / ciliary basal body / midbody / Regulation of TP53 Activity through Phosphorylation / basolateral plasma membrane / molecular adaptor activity / protein kinase activity / protein phosphorylation / non-specific serine/threonine protein kinase / neuron projection / protein heterodimerization activity / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / protein kinase binding / perinuclear region of cytoplasm / nucleoplasm / ATP binding / nucleus / cytosol
Similarity search - Function
TPX2 / Aurora-A binding / TPX2, C-terminal / TPX2 central domain / Targeting protein for Xklp2 (TPX2) domain / Aurora-A binding / Cell cycle regulated microtubule associated protein / Aurora kinase A / Aurora kinase / Phosphorylase Kinase; domain 1 ...TPX2 / Aurora-A binding / TPX2, C-terminal / TPX2 central domain / Targeting protein for Xklp2 (TPX2) domain / Aurora-A binding / Cell cycle regulated microtubule associated protein / Aurora kinase A / Aurora kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-VX6 / Aurora kinase A / Targeting protein for Xklp2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsZhao, B. / Smallwood, A. / Lai, Z.
CitationJournal: Protein Sci. / Year: 2008
Title: Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2.
Authors: Zhao, B. / Smallwood, A. / Yang, J. / Koretke, K. / Nurse, K. / Calamari, A. / Kirkpatrick, R.B. / Lai, Z.
History
DepositionAug 13, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 28, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase 6
B: Targeting protein for Xklp2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7194
Polymers36,1582
Non-polymers5612
Water1,04558
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2660 Å2
ΔGint-16.1 kcal/mol
Surface area14820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.186, 89.097, 88.499
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 31173.727 Da / Num. of mol.: 1 / Fragment: Residues 122-403
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AURKA, AIK, ARK1, AURA, BTAK, STK15, STK6 / Plasmid: pDest17 tev Aurora A 125-391 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Protein/peptide Targeting protein for Xklp2 / TPX2 / Restricted expression proliferation-associated protein 100 / p100 / Differentially expressed ...TPX2 / Restricted expression proliferation-associated protein 100 / p100 / Differentially expressed in cancerous and non-cancerous lung cells 2 / DIL-2 / Protein fls353 / Hepatocellular carcinoma-associated antigen 519


Mass: 4984.162 Da / Num. of mol.: 1 / Fragment: Residues 1-43
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TPX2, C20orf1, C20orf2, DIL2, HCA519 / Plasmid: pDest17 tev Aurora A 125-391 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: Q9ULW0
#3: Chemical ChemComp-VX6 / CYCLOPROPANECARBOXYLIC ACID {4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE


Mass: 464.586 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28N8OS
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 58 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.28 Å3/Da / Density % sol: 46.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.9
Details: 16% PEG 3350 and 0.2 M Lithium sulfate buffered with 100 mM Bis-Tris, pH 6.9, VAPOR DIFFUSION, SITTING DROP, temperature 293.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Feb 20, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 15823 / Num. obs: 15365 / % possible obs: 97.1 % / Observed criterion σ(I): 2 / Redundancy: 5.6 % / Rmerge(I) obs: 0.072 / Rsym value: 0.062 / Net I/σ(I): 25.6
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.409 / Mean I/σ(I) obs: 2.7 / Num. unique all: 1215 / Rsym value: 0.272 / % possible all: 78.2

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Processing

Software
NameVersionClassification
REFMAC5.3.0006refinement
ADSCQuantumdata collection
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1OL5

1ol5


Resolution: 2.3→25 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.926 / SU B: 20.125 / SU ML: 0.232 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.487 / ESU R Free: 0.28 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25585 833 6.1 %RANDOM
Rwork0.20318 ---
obs0.20628 12814 87.32 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 52.914 Å2
Baniso -1Baniso -2Baniso -3
1-4.61 Å20 Å20 Å2
2---4.1 Å20 Å2
3----0.51 Å2
Refinement stepCycle: LAST / Resolution: 2.3→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2437 0 38 58 2533
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0222541
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6591.9823434
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7565293
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.28123.065124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.50415433
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9671521
X-RAY DIFFRACTIONr_chiral_restr0.0990.2360
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021971
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2250.21167
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3160.21713
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1790.2112
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1720.226
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3480.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7421.51524
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.23922389
X-RAY DIFFRACTIONr_scbond_it2.1531167
X-RAY DIFFRACTIONr_scangle_it3.3814.51042
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 61 -
Rwork0.266 709 -
obs--68.93 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.6118-0.03880.41471.27950.0572.272-0.00330.11860.1066-0.13060.0089-0.0564-0.06140.0592-0.0057-0.1169-0.02480.0408-0.14520.0429-0.104335.581129.449611.1252
22.64040.7602-1.19173.1352-0.70632.3875-0.06750.145-0.2026-0.21450.05060.02070.2305-0.05440.0169-0.134-0.0366-0.0337-0.108-0.0331-0.060621.7397.739516.2842
31.1103-2.715-0.97027.63310.10166.03620.11851.05430.3923-0.3527-0.3477-0.3617-0.07150.34160.2292-0.1101-0.12040.0377-0.04060.0813-0.05338.214330.24712.2321
48.93883.70353.78753.42995.46529.61280.55651.5795-0.19-1.1112-0.15850.3550.4492-0.3386-0.3980.3617-0.07840.19380.43120.09660.241334.093616.2306-6.2667
545.088-28.1176-28.93628.90268.559426.48520.0256-0.93270.37930.12530.5374-0.06990.0847-0.0826-0.563-0.2962-0.0671-0.1385-0.16550.0067-0.05625.720327.215518.4512
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA125 - 2124 - 91
2X-RAY DIFFRACTION2AA213 - 38992 - 268
3X-RAY DIFFRACTION3BB6 - 216 - 21
4X-RAY DIFFRACTION4BB26 - 4226 - 42
5X-RAY DIFFRACTION5AC500

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