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- PDB-3umw: Crystal structure of Pim1 kinase in complex with inhibitor (Z)-2-... -

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Basic information

Entry
Database: PDB / ID: 3umw
TitleCrystal structure of Pim1 kinase in complex with inhibitor (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one
ComponentsProto-oncogene serine/threonine-protein kinase pim-1
KeywordsTRANSFERASE/INHIBITOR / PIM1 / kinase inhibitor / rational drug design / leukemia / TRANSFERASE-INHIBITOR complex
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 / ribosomal small subunit binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / 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 / ribosomal small subunit binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / 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
Chem-596 / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.08 Å
AuthorsParker, L.J. / Handa, N. / Yokoyama, S.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Rational evolution of a novel type of potent and selective proviral integration site in Moloney murine leukemia virus kinase 1 (PIM1) inhibitor from a screening-hit compound.
Authors: Nakano, H. / Saito, N. / Parker, L.J. / Tada, Y. / Abe, M. / Tsuganezawa, K. / Yokoyama, S. / Tanaka, A. / Kojima, H. / Okabe, T. / Nagano, T.
History
DepositionNov 14, 2011Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 3, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 1, 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: Proto-oncogene serine/threonine-protein kinase pim-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7664
Polymers34,1881
Non-polymers5793
Water4,270237
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)98.280, 98.280, 80.641
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65

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Components

#1: Protein Proto-oncogene serine/threonine-protein kinase pim-1


Mass: 34187.727 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN (UNP RESIDUES 120-404)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: pim1 / Plasmid: pCR2.1-TOPO / Production host: cell-free protein synthesis (unknown)
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-596 / (2Z)-2-(1H-indazol-3-ylmethylidene)-6-methoxy-7-(piperazin-1-ylmethyl)-1-benzofuran-3(2H)-one


Mass: 390.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22N4O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 237 / 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: 3.29 Å3/Da / Density % sol: 62.6 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 100mM Citrate buffer pH 5.5, 200mM NaCl, 1M NH4HPO4, vapor diffusion, hanging drop, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL26B2 / Wavelength: 1 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Jan 24, 2011
RadiationMonochromator: Fixed exit Si double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.08→32.174 Å / Num. all: 26602 / Num. obs: 26602 / % possible obs: 99.7 % / Redundancy: 6.4 % / Biso Wilson estimate: 29.1 Å2 / Rmerge(I) obs: 0.078 / Rsym value: 0.078 / Net I/σ(I): 6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) allRmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.08-2.196.40.4250.39122476738880.1660.4250.3915.1100
2.19-2.336.40.2890.2662.62326436530.1130.2890.2667.4100
2.33-2.496.40.1970.1814.22205534470.0770.1970.18110.1100
2.49-2.696.40.1440.1325.62059332140.0560.1440.13212.8100
2.69-2.946.40.0980.098.21905429590.0380.0980.0917.699.9
2.94-3.296.40.090.0837.71722526780.0350.090.08323.499.8
3.29-3.86.40.0860.0797.51518723620.0330.0860.07930.499.6
3.8-4.656.50.060.0558.11288119940.0230.060.0553699.4
4.65-6.586.40.0340.03117.9994115490.0130.0340.03137.899
6.58-32.1746.20.030.02714.553078580.0120.030.02739.797.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALA3.2.25data scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3A99

3a99


Resolution: 2.08→32.17 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.945 / WRfactor Rfree: 0.2053 / WRfactor Rwork: 0.1765 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8882 / SU B: 3.111 / SU ML: 0.085 / SU R Cruickshank DPI: 0.1453 / SU Rfree: 0.1316 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.132 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES
RfactorNum. reflection% reflectionSelection details
Rfree0.2003 1346 5.1 %RANDOM
Rwork0.1735 ---
obs0.1749 26602 99.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 63.95 Å2 / Biso mean: 30.2034 Å2 / Biso min: 5.97 Å2
Baniso -1Baniso -2Baniso -3
1-0.63 Å20.32 Å2-0 Å2
2--0.63 Å2-0 Å2
3----0.95 Å2
Refinement stepCycle: LAST / Resolution: 2.08→32.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2131 0 40 237 2408
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0212255
X-RAY DIFFRACTIONr_angle_refined_deg1.5061.9693068
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.55270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.03623.036112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.18215366
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6231520
X-RAY DIFFRACTIONr_chiral_restr0.0890.2325
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211740
X-RAY DIFFRACTIONr_mcbond_it0.8281.51324
X-RAY DIFFRACTIONr_mcangle_it1.59122141
X-RAY DIFFRACTIONr_scbond_it2.2263931
X-RAY DIFFRACTIONr_scangle_it3.6794.5923
LS refinement shellResolution: 2.08→2.134 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.218 96 -
Rwork0.202 1843 -
all-1939 -
obs-1843 100 %

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