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

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Basic information

Entry
Database: PDB / ID: 4uyn
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 / cilium disassembly / spindle pole centrosome / mitotic centrosome separation / histone H3S10 kinase activity / chromosome passenger complex / pronucleus / regulation of G2/M transition of mitotic cell cycle ...Interaction between PHLDA1 and AURKA / regulation of centrosome cycle / axon hillock / cilium disassembly / spindle pole centrosome / mitotic centrosome separation / histone H3S10 kinase activity / chromosome passenger complex / pronucleus / regulation of G2/M transition of mitotic cell cycle / germinal vesicle / meiotic spindle organization / meiotic spindle / spindle organization / positive regulation of mitochondrial fission / mitotic spindle pole / spindle midzone / SUMOylation of DNA replication proteins / negative regulation of protein binding / positive regulation of mitotic cell cycle / positive regulation of mitotic nuclear division / protein serine/threonine/tyrosine kinase activity / centriole / liver regeneration / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / AURKA Activation by TPX2 / regulation of signal transduction by p53 class mediator / molecular function activator activity / mitotic spindle organization / regulation of cytokinesis / G2/M transition of mitotic cell cycle / response to wounding / regulation of protein stability / peptidyl-serine phosphorylation / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / spindle / kinetochore / spindle pole / microtubule cytoskeleton / Regulation of PLK1 Activity at G2/M Transition / protein autophosphorylation / mitotic cell cycle / ciliary basal body / midbody / Regulation of TP53 Activity through Phosphorylation / basolateral plasma membrane / microtubule / protein kinase activity / protein phosphorylation / non-specific serine/threonine protein kinase / postsynaptic density / protein heterodimerization activity / negative regulation of gene expression / protein serine kinase activity / cell division / ubiquitin protein ligase binding / protein serine/threonine kinase activity / centrosome / 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-Y3M / Aurora kinase A
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsCarry, J.C. / Clerc, F. / Minoux, H. / Schio, L. / Mauger, J. / Nair, A. / Parmantier, E. / Lemoigne, R. / Delorme, C. / Nicolas, J.P. ...Carry, J.C. / Clerc, F. / Minoux, H. / Schio, L. / Mauger, J. / Nair, A. / Parmantier, E. / Lemoigne, 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. / Murer, M. / Gontier, S. / Prevost, C. / Monteiro, M.L. / Combeau, C.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Sar156497, an Exquisitely Selective Inhibitor of Aurora Kinases.
Authors: Carry, J. / Clerc, F. / Minoux, H. / Schio, L. / Mauger, J. / Nair, A. / Parmantier, E. / Le Moigne, R. / Delorme, C. / Nicolas, J. / Krick, A. / Abecassis, P. / Crocq-Stuerga, V. / ...Authors: Carry, J. / Clerc, F. / Minoux, H. / Schio, L. / Mauger, J. / Nair, A. / Parmantier, E. / Le Moigne, R. / Delorme, C. / Nicolas, J. / Krick, A. / Abecassis, P. / 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. / Murer, M. / Gontier, S. / Prevost, C. / Monteiro, M. / Combeau, C.
History
DepositionSep 2, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 19, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 21, 2015Group: Database references
Revision 1.2Oct 30, 2019Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Other
Category: database_PDB_caveat / pdbx_database_status ...database_PDB_caveat / pdbx_database_status / pdbx_validate_symm_contact / struct_conn
Item: _pdbx_database_status.status_code_sf
Revision 1.3May 8, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8172
Polymers33,3421
Non-polymers4751
Water1,60389
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.355, 45.913, 59.595
Angle α, β, γ (deg.)90.00, 97.82, 90.00
Int Tables number4
Space group name H-MP1211

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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: 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-Y3M / ethyl (9S)-9-[5-(1H-benzimidazol-2-ylsulfanyl)furan-2-yl]-8-hydroxy-5,6,7,9-tetrahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate


Mass: 474.532 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H22N4O4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 89 / 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: 2.15 Å3/Da / Density % sol: 42.2 % / Description: NONE
Crystal growpH: 8 / Details: PEG3350 21% TRIS 50MM PH 8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9763
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.9→59 Å / Num. obs: 20475 / % possible obs: 99.3 % / Observed criterion σ(I): 2 / Redundancy: 3.5 % / Biso Wilson estimate: 25.41 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 20.8
Reflection shellResolution: 1.9→2.01 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.14 / Mean I/σ(I) obs: 6.3 / % possible all: 97.3

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Processing

Software
NameVersionClassification
BUSTER-TNT2.9.3refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→59 Å / Cor.coef. Fo:Fc: 0.9359 / Cor.coef. Fo:Fc free: 0.9146 / Cross valid method: THROUGHOUT / σ(F): 2 / Details: NONE
RfactorNum. reflection% reflectionSelection details
Rfree0.234 1607 7.8 %RANDOM
Rwork0.201 ---
obs-20466 99.2 %-
Displacement parametersBiso mean: 33.16 Å2
Baniso -1Baniso -2Baniso -3
1-0.5569 Å20 Å20.2632 Å2
2---0.5728 Å20 Å2
3---0.0159 Å2
Refinement stepCycle: LAST / Resolution: 1.9→59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2059 0 34 89 2182
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d21470.032
X-RAY DIFFRACTIONt_angle_deg29002.652
X-RAY DIFFRACTIONt_dihedral_angle_d
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes
X-RAY DIFFRACTIONt_it
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion
X-RAY DIFFRACTIONt_other_torsion
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion
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_contact
LS refinement shellResolution: 1.9→2 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2372 238 8.22 %
Rwork0.2 2657 -
all0.2031 2895 -
obs--99.19 %

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