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- PDB-3fdn: Structure-based drug design of novel Aurora kinase A inhibitors: ... -

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Basic information

Entry
Database: PDB / ID: 3fdn
TitleStructure-based drug design of novel Aurora kinase A inhibitors: Structure basis for potency and specificity
ComponentsSerine/threonine-protein kinase 6Serine/threonine-specific protein kinase
KeywordsTRANSFERASE / Aurora kinase inhibitors / Virtual screening / X-ray co-crystal analysis / Structure-based drug design (SBDD) / H-bonding. / ATP-binding / Cell cycle / Kinase / Nucleotide-binding / Phosphoprotein / Polymorphism / Serine/threonine-protein kinase
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 / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of mitotic nuclear division / mitotic spindle organization / ciliary basal body / negative regulation of protein binding / regulation of signal transduction by p53 class mediator / regulation of cytokinesis / 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 / mitotic 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 / centrosome / protein serine/threonine kinase activity / 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-MMH / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsLeou, J.S. / Wu, J.S. / Coumar, M.S. / Shukla, P. / Hsieh, H.P. / Wu, S.Y.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Structure-based drug design of novel Aurora kinase A inhibitors: structural basis for potency and specificity
Authors: Coumar, M.S. / Leou, J.S. / Shukla, P. / Wu, J.S. / Dixit, A.K. / Lin, W.H. / Chang, C.Y. / Lien, T.W. / Tan, U.K. / Chen, C.H. / Hsu, J.T.A. / Chao, Y.S. / Wu, S.Y. / Hsieh, H.P.
History
DepositionNov 26, 2008Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Sep 15, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 10, 2021Group: Database references / Derived calculations / Category: database_2 / 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
Revision 1.3Nov 1, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)32,7662
Polymers32,3591
Non-polymers4061
Water3,585199
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.613, 81.613, 169.145
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-114-

HOH

21A-452-

HOH

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Components

#1: Protein Serine/threonine-protein kinase 6 / Serine/threonine-specific protein kinase / Aurora kinase A / Aurora-A / Serine/threonine kinase 15 / Aurora/IPL1-related kinase 1 / Aurora- ...Aurora kinase A / Aurora-A / Serine/threonine kinase 15 / Aurora/IPL1-related kinase 1 / Aurora-related kinase 1 / hARK1 / Breast tumor-amplified kinase


Mass: 32359.123 Da / Num. of mol.: 1 / Fragment: catalytic domain / Mutation: T288D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pET28a / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-MMH / N-[3-(acetylamino)phenyl]-5-{(2E)-2-[(4-methoxyphenyl)methylidene]hydrazino}-3-methyl-1H-pyrazole-4-carboxamide / (E)-N-(3-Acetamidophenyl)-5-(2-(4-methoxybenzylidene)hydrazinyl)-3-methyl-1H-pyrazole-4-carboxamide


Mass: 406.438 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22N6O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 199 / 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: 2.51 Å3/Da / Density % sol: 51.05 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 22% PEG400, 0.1mM ammonia sulfate, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL13B1
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 19, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.9→30 Å / Num. obs: 27121 / % possible obs: 98 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Rmerge(I) obs: 0.035 / Net I/σ(I): 28.94
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.467 / Mean I/σ(I) obs: 2.56 / % possible all: 99.3

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREP9.2phasing
REFMAC5.2.0019refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB 1MQ4

1mq4


Resolution: 1.9→30 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.909 / Cross valid method: THROUGHOUT / ESU R: 0.174 / ESU R Free: 0.172 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28696 1335 5 %RANDOM
Rwork0.22762 ---
obs0.23055 25207 98.17 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 39.695 Å2
Baniso -1Baniso -2Baniso -3
1--1.17 Å2-0.59 Å20 Å2
2---1.17 Å20 Å2
3---1.76 Å2
Refinement stepCycle: LAST / Resolution: 1.9→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2134 0 30 199 2363
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222220
X-RAY DIFFRACTIONr_angle_refined_deg1.4131.9783000
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1325259
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.75423.084107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.34415388
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2991518
X-RAY DIFFRACTIONr_chiral_restr0.0950.2317
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021701
X-RAY DIFFRACTIONr_nbd_refined0.2450.21176
X-RAY DIFFRACTIONr_nbtor_refined0.3120.21499
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.230.2223
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2890.246
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.5530.226
X-RAY DIFFRACTIONr_mcbond_it0.9311.51301
X-RAY DIFFRACTIONr_mcangle_it1.72422097
X-RAY DIFFRACTIONr_scbond_it2.2573919
X-RAY DIFFRACTIONr_scangle_it3.7854.5903
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
Num. reflection% reflection
Rfree82 -
Rwork1841 -
obs-99.12 %

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