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- PDB-3vap: Synthesis and SAR Studies of imidazo-[1,2-a]-pyrazine Aurora kina... -

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Basic information

Entry
Database: PDB / ID: 3vap
TitleSynthesis and SAR Studies of imidazo-[1,2-a]-pyrazine Aurora kinase inhibitors with improved off target kinase selectivity
ComponentsAurora kinase A
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / cell cycle / inhibitor / transferase / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / mitotic spindle organization / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of mitotic nuclear division / ciliary basal body / negative regulation of protein binding / regulation of cytokinesis / regulation of signal transduction by p53 class mediator / 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 / 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 / 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-0FY / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.66 Å
AuthorsVoss, M.E. / Rainka, M.P. / Fleming, M. / Peterson, L.H. / Belanger, D.B. / Siddiqui, M.A. / Hruza, A. / Voigt, J. / Basso, A.D. / Gray, K.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Synthesis and SAR studies of imidazo-[1,2-a]-pyrazine Aurora kinase inhibitors with improved off-target kinase selectivity.
Authors: Voss, M.E. / Rainka, M.P. / Fleming, M. / Peterson, L.H. / Belanger, D.B. / Siddiqui, M.A. / Hruza, A. / Voigt, J. / Gray, K. / Basso, A.D.
History
DepositionDec 29, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 2, 2012Provider: repository / Type: Initial release
Revision 1.1May 23, 2012Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / software / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name / _struct_ref_seq_dif.details / _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)32,0042
Polymers31,4401
Non-polymers5641
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)83.329, 83.329, 157.700
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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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: 31440.150 Da / Num. of mol.: 1 / Fragment: UNP Residues 125-391
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: PDEST14 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-0FY / 3-(1-{2-[(3-fluoropyridinium-4-yl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)-6-methyl-8-[(3-{[(1R,3R)-3-methylpiperidinium-1-yl]methyl}-1,2-thiazol-5-yl)amino]imidazo[1,2-a]pyrazin-1-ium


Mass: 563.673 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32FN10OS

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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: 2.51 Å3/Da / Density % sol: 51.06 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8.3
Details: 0.1M TRIS, 0.2M LISO4, 33% PEG 400, 0.001M COMPOUND, 1% DMSO, pH 8.3, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jul 18, 2007 / Details: OSMIC
RadiationMonochromator: OSMIC / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
11.54181
21.54181
ReflectionResolution: 2.659→28.9 Å / Num. obs: 9765 / % possible obs: 98.7 % / Observed criterion σ(I): 3 / Redundancy: 6.8 % / Biso Wilson estimate: 76.72 Å2 / Net I/σ(I): 31.3
Reflection shellResolution: 2.659→2.668 Å / Redundancy: 6.7 % / Rmerge(I) obs: 0.615 / Mean I/σ(I) obs: 3 / Rsym value: 0.615 / % possible all: 100

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Processing

Software
NameVersionClassification
StructureStudiodata collection
BUSTER2.11.2refinement
autoPROCdata scaling
XDS(VERSION December 6data reduction
SCALAdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.66→28.9 Å / Cor.coef. Fo:Fc: 0.9338 / Cor.coef. Fo:Fc free: 0.9108 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber / Details: Afitt used to fit compound in difference density
RfactorNum. reflection% reflectionSelection details
Rfree0.2465 499 5.12 %RANDOM
Rwork0.2022 ---
obs0.2046 9754 98.73 %-
Displacement parametersBiso mean: 84.53 Å2
Baniso -1Baniso -2Baniso -3
1--5.3534 Å20 Å20 Å2
2---5.3534 Å20 Å2
3---10.7068 Å2
Refine analyzeLuzzati coordinate error obs: 0.499 Å
Refinement stepCycle: LAST / Resolution: 2.66→28.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2051 0 40 0 2091
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014231HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.097636HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d916SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC2
X-RAY DIFFRACTIONt_gen_planes602HARMONIC5
X-RAY DIFFRACTIONt_it4231HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.97
X-RAY DIFFRACTIONt_other_torsion17.07
X-RAY DIFFRACTIONt_chiral_improper_torsion259SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4488SEMIHARMONIC4
LS refinement shellResolution: 2.66→2.97 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.3038 125 4.57 %
Rwork0.2266 2608 -
all0.2299 2733 -
obs-2733 98.73 %
Refinement TLS params.Method: refined / Origin x: 17.5772 Å / Origin y: 32.9481 Å / Origin z: 7.8563 Å
111213212223313233
T-0.1268 Å20.1814 Å20.0263 Å2-0.1661 Å20.1204 Å2---0.3407 Å2
L4.6677 °2-0.093 °2-0.9834 °2-2.2051 °2-1.183 °2--1.7959 °2
S-0.2012 Å °-0.6122 Å °-0.0024 Å °-0.2878 Å °0.0801 Å °-0.118 Å °0.3218 Å °0.1402 Å °0.1211 Å °
Refinement TLS groupSelection details: { A|* }

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