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- PDB-4uzh: SAR156497 an exquisitely selective inhibitor of Aurora kinases -

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Basic information

Entry
Database: PDB / ID: 4uzh
TitleSAR156497 an exquisitely selective inhibitor of Aurora kinases
ComponentsAURORA 2 KINASE DOMAIN
KeywordsTRANSFERASE
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 / 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 ...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-JVE / Aurora kinase A
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsPouzieux, S. / Maignan, S. / Crenne, J.Y.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Sar156497 an Exquisitely Selective Inhibitor of Aurora Kinases.
Authors: Carry, J.C. / Clerc, F.F. / Minoux, H. / Schio, L. / Mauger, J. / Nair, A. / Parmantier, E. / Le Moigne, R. / Delorme, C. / Nicolas, J.P. / Krick, A. / Abecassis, P.Y. / Crocq-Stuerga, V. / ...Authors: Carry, J.C. / Clerc, F.F. / Minoux, H. / Schio, L. / Mauger, J. / Nair, A. / Parmantier, E. / Le Moigne, R. / Delorme, C. / Nicolas, J.P. / Krick, A. / Abecassis, P.Y. / Crocq-Stuerga, V. / Pouzieux, S. / Delarbre, L. / Maignan, S. / Bertrand, T. / Bjergarde, K. / Ma, N. / Lachaud, S. / Guizani, H. / Lebel, R. / Doerflinger, G. / Monget, S. / Perron, S. / Gasse, F. / Angouillant-Boniface, O. / Filoche-Romme, B.J. / Murer, M. / Gontier, S. / Prevost, C. / Monteiro, M.L. / Combeau, C.
History
DepositionSep 5, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 19, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 21, 2015Group: Database references
Revision 1.2May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: AURORA 2 KINASE DOMAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6262
Polymers33,3421
Non-polymers2841
Water2,738152
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.997, 45.585, 59.319
Angle α, β, γ (deg.)90.00, 98.34, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein AURORA 2 KINASE DOMAIN / 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 / AURORA 2 KINASE DOMAIN


Mass: 33342.176 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 125-399
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-JVE / (4S)-4-(2-fluorophenyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b][1,7]naphthyridin-5-one


Mass: 284.288 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H13FN4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 152 / Source method: isolated from a natural source / Formula: H2O

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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 Å3/Da / Density % sol: 38.5 % / Description: NONE
Crystal growpH: 7.5
Details: 28% PEG 400, 200 MM NAACETATE, 5MM DTT, 100 MM TRIS PH 8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 0.931
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.931 Å / Relative weight: 1
ReflectionResolution: 2→39.84 Å / Num. obs: 16871 / % possible obs: 96.8 % / Observed criterion σ(I): 2 / Redundancy: 2.5 % / Biso Wilson estimate: 22.25 Å2 / Rmerge(I) obs: 0.12 / Net I/σ(I): 3.1
Reflection shellResolution: 2→2.11 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.23 / Mean I/σ(I) obs: 2.3 / % possible all: 97.5

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Processing

Software
NameVersionClassification
CNX2000refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2→30 Å / Cross valid method: THROUGHOUT / σ(F): 2
RfactorNum. reflection% reflectionSelection details
Rfree0.235 852 5 %RANDOM
Rwork0.205 ---
obs-16868 2.5 %-
Displacement parametersBiso mean: 28 Å2
Refinement stepCycle: LAST / Resolution: 2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2073 0 21 152 2246
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006
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_deg1.232
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d
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
Xplor fileSerial no: 1 / Param file: LIG.PAR / Topol file: LIG.TOP

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