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- PDB-8c1m: Aurora A kinase in complex with TPX2-inhibitor 2 -

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Basic information

Entry
Database: PDB / ID: 8c1m
TitleAurora A kinase in complex with TPX2-inhibitor 2
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 / histone H3S10 kinase activity / chromosome passenger complex / positive regulation of oocyte maturation / pronucleus ...Interaction between PHLDA1 and AURKA / regulation of centrosome cycle / axon hillock / spindle assembly involved in female meiosis I / cilium disassembly / spindle pole centrosome / histone H3S10 kinase activity / chromosome passenger complex / positive regulation of oocyte maturation / pronucleus / mitotic centrosome separation / meiotic spindle / germinal vesicle / protein localization to centrosome / anterior/posterior axis specification / centrosome localization / spindle organization / neuron projection extension / positive regulation of mitochondrial fission / mitotic spindle pole / SUMOylation of DNA replication proteins / spindle midzone / regulation of G2/M transition of mitotic cell cycle / protein serine/threonine/tyrosine kinase activity / centriole / AURKA Activation by TPX2 / positive regulation of mitotic nuclear division / positive regulation of mitotic cell cycle / mitotic spindle organization / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / ciliary basal body / regulation of cytokinesis / regulation of signal transduction by p53 class mediator / negative regulation of protein binding / 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 / 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 / peptidyl-serine phosphorylation / basolateral plasma membrane / proteasome-mediated ubiquitin-dependent protein catabolic process / Regulation of TP53 Activity through Phosphorylation / protein autophosphorylation / microtubule / postsynaptic density / non-specific serine/threonine protein kinase / protein kinase activity / protein heterodimerization activity / protein phosphorylation / cell division / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / glutamatergic synapse / ubiquitin protein ligase binding / negative regulation of apoptotic process / 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
ADENOSINE-5'-DIPHOSPHATE / Chem-T4X / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.84 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

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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)32,4385
Polymers31,6641
Non-polymers7744
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1100 Å2
ΔGint-28 kcal/mol
Surface area12510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.82, 82.82, 139
Angle α, β, γ (deg.)90, 90, 90
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 / 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: 31664.256 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
Plasmid: pHAT4 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-T4X / 3-oxidanyl-5-[4-(trifluoromethyloxy)phenyl]benzoic acid


Mass: 298.214 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H9F3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
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: 3.76 Å3/Da / Density % sol: 67.32 %
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: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jul 13, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.84→53.97 Å / Num. obs: 11913 / % possible obs: 99 % / Redundancy: 12.4 % / CC1/2: 1 / Rmerge(I) obs: 0.068 / Rpim(I) all: 0.021 / Net I/σ(I): 25.5
Reflection shellResolution: 2.84→2.91 Å / Rmerge(I) obs: 0.828 / Mean I/σ(I) obs: 3.7 / Num. unique obs: 847 / CC1/2: 0.963 / Rpim(I) all: 0.234 / Rrim(I) all: 0.861

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Processing

Software
NameVersionClassification
BUSTER2.10.4refinement
XDSdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.84→53.97 Å / Cor.coef. Fo:Fc: 0.88 / Cor.coef. Fo:Fc free: 0.895 / SU R Cruickshank DPI: 0.613 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.629 / SU Rfree Blow DPI: 0.328 / SU Rfree Cruickshank DPI: 0.33
RfactorNum. reflection% reflectionSelection details
Rfree0.269 584 -RANDOM
Rwork0.252 ---
obs0.2529 11861 98.9 %-
Displacement parametersBiso mean: 82.35 Å2
Baniso -1Baniso -2Baniso -3
1--17.0887 Å20 Å20 Å2
2---17.0887 Å20 Å2
3---34.1775 Å2
Refine analyzeLuzzati coordinate error obs: 0.46 Å
Refinement stepCycle: LAST / Resolution: 2.84→53.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2161 0 50 0 2211
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0062266HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.873073HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d798SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes378HARMONIC5
X-RAY DIFFRACTIONt_it2266HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion278SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1577SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.55
X-RAY DIFFRACTIONt_other_torsion19.5
LS refinement shellResolution: 2.84→2.88 Å
RfactorNum. reflection% reflection
Rfree0.5591 25 -
Rwork0.2993 --
obs0.3141 409 100 %

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