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- PDB-8c1e: Aurora A kinase in complex with TPX2-inhibitor 9 -

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Basic information

Entry
Database: PDB / ID: 8c1e
TitleAurora A kinase in complex with TPX2-inhibitor 9
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 / 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
ADENOSINE-5'-TRIPHOSPHATE / Chem-T0X / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.798 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: J.Med.Chem. / Year: 2024
Title: Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents.
Authors: Stockwell, S.R. / Scott, D.E. / Fischer, G. / Guarino, E. / Rooney, T.P.C. / Feng, T.S. / Moschetti, T. / Srinivasan, R. / Alza, E. / Asteian, A. / Dagostin, C. / Alcaide, A. / Rocaboy, M. / ...Authors: Stockwell, S.R. / Scott, D.E. / Fischer, G. / Guarino, E. / Rooney, T.P.C. / Feng, T.S. / Moschetti, T. / Srinivasan, R. / Alza, E. / Asteian, A. / Dagostin, C. / Alcaide, A. / Rocaboy, M. / Blaszczyk, B. / Higueruelo, A. / Wang, X. / Rossmann, M. / Perrior, T.R. / Blundell, T.L. / Spring, D.R. / McKenzie, G. / Abell, C. / Skidmore, J. / Venkitaraman, A.R. / Hyvonen, M.
History
DepositionDec 20, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 10, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Sep 25, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)32,3784
Polymers31,5361
Non-polymers8423
Water1,31573
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1060 Å2
ΔGint-14 kcal/mol
Surface area12210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.037, 82.037, 135.867
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Aurora kinase A / Aurora 2 / Aurora/IPL1-related kinase 1 / hARK1 / Breast tumor-amplified kinase / Serine/threonine- ...Aurora 2 / Aurora/IPL1-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: 31536.131 Da / Num. of mol.: 1 / Fragment: Aurora A kinase
Source method: isolated from a genetically manipulated source
Details: GSMGS is part of expression fusion / Source: (gene. exp.) Homo sapiens (human)
Gene: AURKA, AIK, AIRK1, ARK1, AURA, AYK1, BTAK, IAK1, STK15, STK6
Plasmid: pHAT4 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-T0X / 4-(4-chloranyl-3-cyano-phenyl)-7-methyl-1~{H}-indole-6-carboxylic acid


Mass: 310.734 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H11ClN2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 73 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 3.62 Å3/Da / Density % sol: 66.06 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6.5
Details: 5% DMSO, 0.2M MgSO4, 0.05 M HEPES 7.4: soaking: 0.2M MgSO4, 0.05M HEPES 7.4, 30% glycerol, 10% DMSO, 5 mM compound

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9801 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 15, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9801 Å / Relative weight: 1
ReflectionResolution: 2.798→135.867 Å / Num. obs: 12082 / % possible obs: 100 % / Redundancy: 6.9 % / CC1/2: 0.994 / Rmerge(I) obs: 0.167 / Rpim(I) all: 0.069 / Rrim(I) all: 0.181 / Net I/σ(I): 14 / Num. measured all: 83838
Reflection shellResolution: 2.798→2.808 Å / Redundancy: 7.2 % / Rmerge(I) obs: 1.157 / Num. unique obs: 135 / CC1/2: 0.548 / Rpim(I) all: 0.468 / Rrim(I) all: 1.25 / % possible all: 100

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Processing

Software
NameVersionClassification
Aimlessdata scaling
REFMAC5.8.0073refinement
PDB_EXTRACT3.23data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.798→70.23 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.9 / SU B: 10.957 / SU ML: 0.217 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.489 / ESU R Free: 0.304 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2388 610 5.1 %RANDOM
Rwork0.1726 ---
obs0.1758 11418 99.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 171.17 Å2 / Biso mean: 48.803 Å2 / Biso min: 17.38 Å2
Baniso -1Baniso -2Baniso -3
1--0.09 Å20 Å20 Å2
2---0.09 Å20 Å2
3---0.18 Å2
Refinement stepCycle: final / Resolution: 2.798→70.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2152 0 54 73 2279
Biso mean--41.34 47.21 -
Num. residues----262
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0192263
X-RAY DIFFRACTIONr_angle_refined_deg2.1021.9973071
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1535261
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.05322.71107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.62515390
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5271520
X-RAY DIFFRACTIONr_chiral_restr0.1190.2325
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211787
LS refinement shellResolution: 2.798→2.871 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.332 48 -
Rwork0.238 819 -
all-867 -
obs--100 %

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