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

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Basic information

Entry
Database: PDB / ID: 4uzd
TitleSAR156497 an exquisitely selective inhibitor of Aurora kinases
ComponentsAURORA KINASE A
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 / positive regulation of oocyte maturation / spindle pole centrosome / 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 / positive regulation of oocyte maturation / spindle pole centrosome / 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 / 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 / centriole / protein serine/threonine/tyrosine kinase activity / positive regulation of mitotic cell cycle / positive regulation of mitotic nuclear division / AURKA Activation by TPX2 / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / mitotic spindle organization / 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 / spindle microtubule / 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 / basolateral plasma membrane / peptidyl-serine phosphorylation / proteasome-mediated ubiquitin-dependent protein catabolic process / Regulation of TP53 Activity through Phosphorylation / protein autophosphorylation / postsynaptic density / non-specific serine/threonine protein kinase / protein kinase activity / protein heterodimerization activity / cell division / protein phosphorylation / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / 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-QMN / Aurora kinase A
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsPouzieux, S. / Delarbre, L. / 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 14, 2015Group: Refinement description
Revision 1.2Jan 21, 2015Group: Database references
Revision 1.3Aug 21, 2019Group: Data collection / Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen ...pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Revision 1.4May 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

Downloads & links

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Assembly

Deposited unit
A: AURORA KINASE A
B: AURORA KINASE A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,5934
Polymers66,6562
Non-polymers9372
Water00
1
A: AURORA KINASE A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7972
Polymers33,3281
Non-polymers4691
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: AURORA KINASE A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7972
Polymers33,3281
Non-polymers4691
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)90.450, 90.450, 206.880
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121
Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (1, 0.022, -0.004), (0.004, -0.007, 1), (0.022, -1, -0.007)
Vector: -0.153, -68.949, 68.169)

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Components

#1: Protein AURORA KINASE A / 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


Mass: 33328.191 Da / Num. of mol.: 2 / 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-QMN / ethyl (9S)-9-[3-(1H-benzimidazol-2-yloxy)phenyl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate


Mass: 468.504 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H24N4O4

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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: 3.66 Å3/Da / Density % sol: 68 % / Description: NONE
Crystal growpH: 7 / Details: 4% PEG 4000, 50 MM HEPES PH 7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.9762
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 3.2→78.3 Å / Num. obs: 16476 / % possible obs: 97.9 % / Observed criterion σ(I): 2 / Redundancy: 5.8 % / Biso Wilson estimate: 117.47 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 19.9
Reflection shellResolution: 3.2→3.37 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.41 / Mean I/σ(I) obs: 3.1 / % possible all: 99.3

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 3.2→78.33 Å / Cor.coef. Fo:Fc: 0.9142 / Cor.coef. Fo:Fc free: 0.8679 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.423
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.262 1270 7.73 %RANDOM
Rwork0.215 ---
obs-16434 97.61 %-
Displacement parametersBiso mean: 94.63 Å2
Baniso -1Baniso -2Baniso -3
1--11.2179 Å20 Å20 Å2
2---11.2179 Å20 Å2
3---22.4359 Å2
Refine analyzeLuzzati coordinate error obs: 0.707 Å
Refinement stepCycle: LAST / Resolution: 3.2→78.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4217 0 70 0 4287
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014397HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.055943HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1577SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes98HARMONIC2
X-RAY DIFFRACTIONt_gen_planes700HARMONIC5
X-RAY DIFFRACTIONt_it4397HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.59
X-RAY DIFFRACTIONt_other_torsion18.64
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion535SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5088SEMIHARMONIC4
LS refinement shellResolution: 3.2→3.42 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2827 255 8.63 %
Rwork0.2577 2701 -
all0.2598 2956 -
obs--97.61 %

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