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- PDB-3r21: Design, synthesis, and biological evaluation of pyrazolopyridine-... -

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Entry
Database: PDB / ID: 3r21
TitleDesign, synthesis, and biological evaluation of pyrazolopyridine-sulfonamides as potent multiple-mitotic kinase (MMK) inhibitors (Part I)
ComponentsSerine/threonine-protein kinase 6Serine/threonine-specific protein kinase
Keywordstransferase/transferase inhibitor / Kinase domain / 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 / 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-D36 / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsZhang, L. / Fan, J. / Chong, J.-H. / Cesena, A. / Tam, B. / Gilson, C. / Boykin, C. / Wang, D. / Marcotte, D. / Le Brazidec, J.-Y. ...Zhang, L. / Fan, J. / Chong, J.-H. / Cesena, A. / Tam, B. / Gilson, C. / Boykin, C. / Wang, D. / Marcotte, D. / Le Brazidec, J.-Y. / Aivazian, D. / Piao, J. / Lundgren, K. / Hong, K. / Vu, K. / Nguyen, K.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Design, synthesis, and biological evaluation of pyrazolopyrimidine-sulfonamides as potent multiple-mitotic kinase (MMK) inhibitors (part I).
Authors: Zhang, L. / Fan, J. / Chong, J.H. / Cesena, A. / Tam, B.Y. / Gilson, C. / Boykin, C. / Wang, D. / Aivazian, D. / Marcotte, D. / Xiao, G. / Le Brazidec, J.Y. / Piao, J. / Lundgren, K. / Hong, ...Authors: Zhang, L. / Fan, J. / Chong, J.H. / Cesena, A. / Tam, B.Y. / Gilson, C. / Boykin, C. / Wang, D. / Aivazian, D. / Marcotte, D. / Xiao, G. / Le Brazidec, J.Y. / Piao, J. / Lundgren, K. / Hong, K. / Vu, K. / Nguyen, K. / Gan, L.S. / Silvian, L. / Ling, L. / Teng, M. / Reff, M. / Takeda, N. / Timple, N. / Wang, Q. / Morena, R. / Khan, S. / Zhao, S. / Li, T. / Lee, W.C. / Taveras, A.G. / Chao, J.
History
DepositionMar 11, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 10, 2011Provider: repository / Type: Initial release
Revision 1.1Feb 29, 2012Group: Database references
Revision 1.2Sep 13, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)31,8163
Polymers31,3471
Non-polymers4692
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)82.210, 82.210, 165.700
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 Serine/threonine-protein kinase 6 / Serine/threonine-specific protein kinase / Aurora kinase A / Aurora/IPL1-related kinase 1 / ARK-1 / Aurora-related kinase 1 / hARK1 / Breast ...Aurora kinase A / 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 aurora-A


Mass: 31346.939 Da / Num. of mol.: 1 / Fragment: unp residues 126-391 / Mutation: T287D, T288D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AIK, ARK1, AURA, AURKA, BTAK, STK15, STK6 / Plasmid: pDEST20 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-D36 / N-(2-aminoethyl)-N-{5-[(1-cycloheptyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]pyridin-2-yl}methanesulfonamide


Mass: 444.554 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H28N8O2S
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg

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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: 2.58 Å3/Da / Density % sol: 52.29 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 10% Peg550 MME, 100mM Tris, 10% ethylene glycol, pH 9, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 193 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.9793 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Jun 11, 2008 / Details: Diamond(111)monochromator
RadiationMonochromator: Diamond (111) monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 7898 / % possible obs: 99.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 10 % / Biso Wilson estimate: 90.8268 Å2 / Rmerge(I) obs: 0.063 / Net I/σ(I): 40.2
Reflection shellResolution: 2.9→3 Å / Redundancy: 10.3 % / Rmerge(I) obs: 0.696 / Mean I/σ(I) obs: 2.9 / Num. unique all: 754 / % possible all: 100

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
REFMAC5.5.0109refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2W1C

2w1c


Resolution: 2.9→25 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.895 / SU B: 18.424 / SU ML: 0.323 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / ESU R Free: 0.102 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.30467 357 4.6 %RANDOM
Rwork0.258 ---
obs0.26 7427 99.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 81.871 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å20 Å20 Å2
2---0.03 Å20 Å2
3---0.07 Å2
Refinement stepCycle: LAST / Resolution: 2.9→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2074 0 32 0 2106
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0222164
X-RAY DIFFRACTIONr_angle_refined_deg1.8051.9882926
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.385254
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.21323.01103
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.42615383
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.9061518
X-RAY DIFFRACTIONr_chiral_restr0.1110.2314
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211633
X-RAY DIFFRACTIONr_mcbond_it0.8471.51268
X-RAY DIFFRACTIONr_mcangle_it1.54522044
X-RAY DIFFRACTIONr_scbond_it1.9813896
X-RAY DIFFRACTIONr_scangle_it3.3334.5881
LS refinement shellResolution: 2.904→2.978 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 23 -
Rwork0.271 518 -
obs-426 97.65 %

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