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- PDB-3nrm: Imidazo[1,2-a]pyrazine-based Aurora Kinase Inhibitors -

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Basic information

Entry
Database: PDB / ID: 3nrm
TitleImidazo[1,2-a]pyrazine-based Aurora Kinase Inhibitors
ComponentsSerine/threonine-protein kinase 6Serine/threonine-specific protein kinase
KeywordsTRANSFERASE / KINASE / CELL CYCLE / INHIBITOR
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 / 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 / AURKA Activation by TPX2 / mitotic spindle organization / positive regulation of mitotic nuclear division / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / ciliary basal body / regulation of cytokinesis / negative regulation of protein binding / 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 / spindle microtubule / regulation of protein stability / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / spindle / kinetochore / mitotic spindle / 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 / basolateral plasma membrane / proteasome-mediated ubiquitin-dependent protein catabolic process / peptidyl-serine phosphorylation / 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-NRM / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 3.05 Å
AuthorsHruza, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Discovery of imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors.
Authors: Belanger, D.B. / Curran, P.J. / Hruza, A. / Voigt, J. / Meng, Z. / Mandal, A.K. / Siddiqui, M.A. / Basso, A.D. / Gray, K.
History
DepositionJun 30, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 18, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: 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 / pdbx_initial_refinement_model / 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 / _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

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Assembly

Deposited unit
A: Serine/threonine-protein kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8562
Polymers32,5581
Non-polymers2971
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)81.890, 81.890, 169.271
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 Serine/threonine-protein kinase 6 / Serine/threonine-specific protein kinase / Aurora kinase A / Serine/threonine-protein kinase aurora-A / Serine/threonine-protein kinase 15 / ...Aurora kinase A / Serine/threonine-protein kinase aurora-A / Serine/threonine-protein kinase 15 / Aurora/IPL1-related kinase 1 / Aurora-related kinase 1 / ARK-1 / hARK1 / Breast tumor-amplified kinase


Mass: 32558.311 Da / Num. of mol.: 1 / Fragment: UNP residues 126-403 / Mutation: T287A, T288A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AURKA, AIK, ARK1, AURA, BTAK, STK15, STK6 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-NRM / N-(3-methylisothiazol-5-yl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine


Mass: 297.338 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H11N7S

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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: 2.52 Å3/Da / Density % sol: 51.11 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1 M MES, 0.2 M MGSO4, 18-26% MME-PEG-5000, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: May 25, 2006 / Details: OSMIC
RadiationMonochromator: OSMIC / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 3.05→26 Å / Num. all: 6980 / Num. obs: 6615 / % possible obs: 95.1 % / Observed criterion σ(I): 1.9 / Redundancy: 4 % / Biso Wilson estimate: 101.72 Å2 / Rmerge(I) obs: 0.097 / Net I/σ(I): 10.8
Reflection shellResolution: 3.05→3.16 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.522 / Mean I/σ(I) obs: 1.9 / Num. unique all: 639 / % possible all: 94.9

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Processing

Software
NameVersionClassification
CrystalCleardata collection
BUSTER2.9.3refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 1MQ4

1mq4


Resolution: 3.05→23.23 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.902 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2582 350 5.32 %RANDOM
Rwork0.2204 ---
obs0.2225 6583 95.57 %-
all-6980 --
Displacement parametersBiso mean: 85.3 Å2
Baniso -1Baniso -2Baniso -3
1-11.3148 Å20 Å20 Å2
2--11.3148 Å20 Å2
3----22.6296 Å2
Refine analyzeLuzzati coordinate error obs: 0.657 Å
Refinement stepCycle: LAST / Resolution: 3.05→23.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2155 0 21 0 2176
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.00822332
X-RAY DIFFRACTIONt_angle_deg1.0330072
X-RAY DIFFRACTIONt_dihedral_angle_d7832
X-RAY DIFFRACTIONt_trig_c_planes492
X-RAY DIFFRACTIONt_gen_planes3245
X-RAY DIFFRACTIONt_it223320
X-RAY DIFFRACTIONt_omega_torsion2.11
X-RAY DIFFRACTIONt_other_torsion20.81
X-RAY DIFFRACTIONt_chiral_improper_torsion2715
X-RAY DIFFRACTIONt_ideal_dist_contact25324
Refinement TLS params.Method: refined / Origin x: 16.8069 Å / Origin y: 31.6839 Å / Origin z: 7.8393 Å
111213212223313233
T0.0425 Å20.03 Å20.0005 Å2--0.0483 Å2-0.1023 Å2--0.0295 Å2
L2.7263 °20.8682 °2-1.2135 °2-1.4378 °2-1.732 °2--0.7724 °2
S0.0041 Å °-0.1269 Å °-0.062 Å °0.01 Å °0.0744 Å °-0.0752 Å °0.0339 Å °0.0423 Å °-0.0785 Å °

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