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- PDB-2j50: Structure of Aurora-2 in complex with PHA-739358 -

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Basic information

Entry
Database: PDB / ID: 2j50
TitleStructure of Aurora-2 in complex with PHA-739358
ComponentsSERINE/THREONINE-PROTEIN KINASE 6Serine/threonine-specific protein kinase
KeywordsTRANSFERASE / PHOSPHORYLATION / NUCLEOTIDE-BINDING / KINASE / CELL CYCLE / ATP-BINDING / NUCLEOTIDE- BINDING / SERINE/THREONINE-PROTEIN KINASE / SERINE-THREONINE-PROTEIN KINASE
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 / positive regulation of oocyte maturation / 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 / spindle pole centrosome / positive regulation of oocyte maturation / 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 / positive regulation of mitochondrial fission / spindle organization / 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 / AURKA Activation by TPX2 / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of mitotic nuclear division / mitotic spindle organization / ciliary basal body / negative regulation of protein binding / regulation of signal transduction by p53 class mediator / regulation of cytokinesis / 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 / mitotic spindle / kinetochore / response to wounding / microtubule cytoskeleton / G2/M transition of mitotic cell cycle / Regulation of PLK1 Activity at G2/M Transition / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / mitotic cell cycle / midbody / proteasome-mediated ubiquitin-dependent protein catabolic process / basolateral plasma membrane / peptidyl-serine phosphorylation / Regulation of TP53 Activity through Phosphorylation / microtubule / postsynaptic density / protein autophosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / protein heterodimerization activity / cell division / negative regulation of gene expression / protein phosphorylation / protein serine kinase activity / centrosome / protein serine/threonine kinase activity / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Aurora kinase A / Aurora kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-627 / Aurora kinase A
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsCameron, A.D. / Izzo, G. / Storici, P. / Rusconi, L. / Fancelli, D. / Varasi, M. / Berta, D. / Bindi, S. / Forte, B. / Severino, D. ...Cameron, A.D. / Izzo, G. / Storici, P. / Rusconi, L. / Fancelli, D. / Varasi, M. / Berta, D. / Bindi, S. / Forte, B. / Severino, D. / Tonani, R. / Vianello, P.
CitationJournal: J.Med.Chem. / Year: 2006
Title: 1,4,5,6-Tetrahydropyrrolo[3,4-C]Pyrazoles: Identification of a Potent Aurora Kinase Inhibitor with a Favorable Antitumor Kinase Inhibition Profile.
Authors: Fancelli, D. / Moll, J. / Varasi, M. / Bravo, R. / Artico, R. / Berta, D. / Bindi, S. / Cameron, A.D. / Candiani, I. / Cappella, P. / Carpinelli, P. / Croci, W. / Forte, B. / Giorgini, M.L. ...Authors: Fancelli, D. / Moll, J. / Varasi, M. / Bravo, R. / Artico, R. / Berta, D. / Bindi, S. / Cameron, A.D. / Candiani, I. / Cappella, P. / Carpinelli, P. / Croci, W. / Forte, B. / Giorgini, M.L. / Klapwijk, J. / Marsiglio, A. / Pesenti, E. / Rocchetti, M. / Roletto, F. / Severino, D. / Soncini, C. / Storici, P. / Tonani, R. / Zugnoni, P. / Vianello, P.
History
DepositionSep 8, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 6, 2006Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2015Group: Non-polymer description / Version format compliance
Revision 1.2Apr 3, 2019Group: Data collection / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc / pdbx_database_status
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: SERINE/THREONINE-PROTEIN KINASE 6
B: SERINE/THREONINE-PROTEIN KINASE 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,8796
Polymers64,7382
Non-polymers1,1414
Water0
1
A: SERINE/THREONINE-PROTEIN KINASE 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9403
Polymers32,3691
Non-polymers5712
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: SERINE/THREONINE-PROTEIN KINASE 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9403
Polymers32,3691
Non-polymers5712
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)75.688, 86.782, 86.829
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein SERINE/THREONINE-PROTEIN KINASE 6 / Serine/threonine-specific protein kinase / SERINE/THREONINE KINASE 15 / AURORA/IPL1-RELATED KINASE 1 / AURORA-RELATED KINASE 1 / HARK1 / ...SERINE/THREONINE KINASE 15 / AURORA/IPL1-RELATED KINASE 1 / AURORA-RELATED KINASE 1 / HARK1 / AURORA-A / BREAST-TUMOR-AMPLIFIED KINASE


Mass: 32369.076 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN, RESIDUES 126-403
Source method: isolated from a genetically manipulated source
Details: USING MASS SPECTROMETRY THE PROTEIN WAS SEEN TO BE PARTIALLY PHOSPHORYLATED BUT NO PHOSPHATES WERE SEEN IN THE STRUCTURE
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): High Five / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-627 / N-[(3E)-5-[(2R)-2-METHOXY-2-PHENYLACETYL]PYRROLO[3,4-C]PYRAZOL-3(5H)-YLIDENE]-4-(4-METHYLPIPERAZIN-1-YL)BENZAMIDE / Danusertib / PHA-739358


Mass: 474.555 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H30N6O3
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
Sequence detailsGP IS PRESENT AT START DUE TO CLONING ARTIFACT

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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: 2.5 Å3/Da / Density % sol: 40 %
Crystal growpH: 4.6
Details: 20% PEG 2000MME, 0.2M LITHIUM SULPHATE, 0.1M SODIUM ACETATE PH 4.6, 2% ISOPROPANOL, 2MM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.93
DetectorType: ADSC CCD / Detector: CCD / Date: Sep 6, 2002
RadiationMonochromator: DIAMOND (111), GE(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.93 Å / Relative weight: 1
ReflectionResolution: 3→30 Å / Num. obs: 11903 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 4.7 % / Biso Wilson estimate: 95 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 14
Reflection shellResolution: 3→3.11 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.71 / Mean I/σ(I) obs: 2.4 / % possible all: 100

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Processing

Software
NameVersionClassification
CNX2000refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2J4

Resolution: 3→28.53 Å / Rfactor Rfree error: 0.011 / Isotropic thermal model: GROUP / Cross valid method: THROUGHOUT / σ(F): 0
Details: BULK SOLVENT MODEL USED BY ANALOGY WITH A HIGHER RESOLUTION STRUCTURE THE SPACE GROUP WAS DEFINED AS P212121, HOWEVER THE SPACE GROUP SEEMS TO BE P41212. IN THE HIGHER RESOLUTION STRUCTURE ...Details: BULK SOLVENT MODEL USED BY ANALOGY WITH A HIGHER RESOLUTION STRUCTURE THE SPACE GROUP WAS DEFINED AS P212121, HOWEVER THE SPACE GROUP SEEMS TO BE P41212. IN THE HIGHER RESOLUTION STRUCTURE THE SYMMETRY BROKE DOWN AT HIGHER RESOLUTION. THE STRUCTURE WAS REFINED WITH STRICT NCS.
RfactorNum. reflection% reflectionSelection details
Rfree0.268 609 5.1 %RANDOM
Rwork0.221 ---
obs-11862 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 52.2479 Å2 / ksol: 0.333771 e/Å3
Displacement parametersBiso mean: 66.5 Å2
Baniso -1Baniso -2Baniso -3
1--6.35 Å20 Å20 Å2
2--2.03 Å20 Å2
3---4.32 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.5 Å0.38 Å
Luzzati d res low-5 Å
Luzzati sigma a0.67 Å0.53 Å
Refinement stepCycle: LAST / Resolution: 3→28.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4084 0 80 0 4164
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.2
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.99
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
Refine LS restraints NCSNCS model details: CONSTR
LS refinement shellResolution: 3→3.19 Å / Rfactor Rfree error: 0.043 / Total num. of bins used: 6
Rfactor% reflection
Rfree0.428 5.2 %
Rwork0.377 -
obs-97.6 %
Xplor fileSerial no: 1 / Param file: PROTEIN.PARAM / Topol file: 358.TOP

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