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- PDB-4as0: Cyclometalated Phthalimides as Protein Kinase Inhibitors -

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Basic information

Entry
Database: PDB / ID: 4as0
TitleCyclometalated Phthalimides as Protein Kinase Inhibitors
ComponentsSERINE/THREONINE-PROTEIN KINASE PIM-1
KeywordsTRANSFERASE / PIM1 / OCTASPORINE / RUTHENIUM / KINASE INHIBITOR
Function / homology
Function and homology information


positive regulation of cardioblast proliferation / regulation of hematopoietic stem cell proliferation / cellular detoxification / vitamin D receptor signaling pathway / STAT5 activation downstream of FLT3 ITD mutants / transcription factor binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / ribosomal small subunit binding / positive regulation of cardiac muscle cell proliferation / positive regulation of TORC1 signaling ...positive regulation of cardioblast proliferation / regulation of hematopoietic stem cell proliferation / cellular detoxification / vitamin D receptor signaling pathway / STAT5 activation downstream of FLT3 ITD mutants / transcription factor binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / ribosomal small subunit binding / positive regulation of cardiac muscle cell proliferation / positive regulation of TORC1 signaling / Signaling by FLT3 fusion proteins / negative regulation of innate immune response / positive regulation of brown fat cell differentiation / protein serine/threonine kinase activator activity / regulation of transmembrane transporter activity / positive regulation of protein serine/threonine kinase activity / negative regulation of DNA-binding transcription factor activity / cellular response to type II interferon / manganese ion binding / Interleukin-4 and Interleukin-13 signaling / protein autophosphorylation / protein stabilization / non-specific serine/threonine protein kinase / cell cycle / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / nucleolus / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Serine/threonine-protein kinase pim-1/2/3 / 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 ...Serine/threonine-protein kinase pim-1/2/3 / 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
PHTALIMIDE-RUTHENIUM COMPLEX / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsBlanck, S. / Geisselbrecht, Y. / Middel, S. / Mietke, T. / Harms, K. / Essen, L.-O. / Meggers, E.
CitationJournal: Dalton Trans / Year: 2012
Title: Bioactive Cyclometalated Phthalimides: Design, Synthesis and Kinase Inhibition.
Authors: Blanck, S. / Geisselbrecht, Y. / Kraling, K. / Middel, S. / Mietke, T. / Harms, K. / Essen, L.-O. / Meggers, E.
History
DepositionApr 27, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 3, 2012Provider: repository / Type: Initial release
Revision 1.1Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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 PIM-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9502
Polymers31,4181
Non-polymers5331
Water2,486138
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.200, 99.200, 80.600
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

#1: Protein SERINE/THREONINE-PROTEIN KINASE PIM-1 / PIM1


Mass: 31417.654 Da / Num. of mol.: 1 / Fragment: RESIDUES 33-305
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PLIC-SGC / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): PLYSS
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-RPS / PHTALIMIDE-RUTHENIUM COMPLEX


Mass: 532.641 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19N2O3RuS3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 138 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsISOFORM-2 MUTATION R250G (GI 33304198)

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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: 3.37 Å3/Da / Density % sol: 63.49 % / Description: NONE
Crystal growpH: 7.5
Details: 200 MM SODIUM CITRATE, 100 MM HEPES, 30 % MPD, PH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8726
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 30, 2011
Details: PT COATED MIRRORS IN A KIRKPATRICK-BAEZ (KB) GEOMETRY
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 2.3→25 Å / Num. obs: 20098 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 6.4 % / Biso Wilson estimate: 28.3 Å2 / Rmerge(I) obs: 0.13 / Net I/σ(I): 16.62
Reflection shellResolution: 2.3→2.4 Å / Redundancy: 6.4 % / Rmerge(I) obs: 0.52 / Mean I/σ(I) obs: 4.81 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3BWF

3bwf


Resolution: 2.3→24.8 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.94 / SU B: 5.164 / SU ML: 0.126 / Cross valid method: THROUGHOUT / ESU R: 0.195 / ESU R Free: 0.164 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY.
RfactorNum. reflection% reflectionSelection details
Rfree0.20127 711 3.5 %RANDOM
Rwork0.1706 ---
obs0.17176 19383 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.991 Å2
Baniso -1Baniso -2Baniso -3
1-1.05 Å20.53 Å20 Å2
2--1.05 Å20 Å2
3----1.58 Å2
Refinement stepCycle: LAST / Resolution: 2.3→24.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2200 0 29 138 2367
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222313
X-RAY DIFFRACTIONr_bond_other_d0.0010.021599
X-RAY DIFFRACTIONr_angle_refined_deg1.4421.9643158
X-RAY DIFFRACTIONr_angle_other_deg0.84533855
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8285276
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.19922.931116
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.83415372
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6741521
X-RAY DIFFRACTIONr_chiral_restr0.0770.2333
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212571
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02508
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.791.51364
X-RAY DIFFRACTIONr_mcbond_other0.1211.5556
X-RAY DIFFRACTIONr_mcangle_it1.5522207
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.1173949
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.614.5949
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.205 42 -
Rwork0.195 1438 -
obs--99.93 %

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