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- PDB-4k18: Structure of PIM-1 kinase bound to 5-(4-cyanobenzyl)-N-(4-fluorop... -

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Basic information

Entry
Database: PDB / ID: 4k18
TitleStructure of PIM-1 kinase bound to 5-(4-cyanobenzyl)-N-(4-fluorophenyl)-7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxamide
ComponentsSerine/threonine-protein kinase pim-1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PIM-1 / kinase domain / Ser/Thr kinase / ATP-competitive / structure-based drug design / phosphorylation / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of cardioblast proliferation / cellular detoxification / regulation of hematopoietic stem cell proliferation / vitamin D receptor signaling pathway / STAT5 activation downstream of FLT3 ITD mutants / ribosomal small subunit binding / transcription factor 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 / cellular detoxification / regulation of hematopoietic stem cell proliferation / vitamin D receptor signaling pathway / STAT5 activation downstream of FLT3 ITD mutants / ribosomal small subunit binding / transcription factor 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 / positive regulation of brown fat cell differentiation / negative regulation of innate immune response / 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 / cytosol / cytoplasm
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-1OB / PHOSPHATE ION / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.051 Å
AuthorsMurray, J.M. / Wallweber, H. / Steffek, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design.
Authors: Wang, X. / Magnuson, S. / Pastor, R. / Fan, E. / Hu, H. / Tsui, V. / Deng, W. / Murray, J. / Steffek, M. / Wallweber, H. / Moffat, J. / Drummond, J. / Chan, G. / Harstad, E. / Ebens, A.J.
History
DepositionApr 4, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 15, 2013Provider: repository / Type: Initial release
Revision 1.1May 22, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)32,4173
Polymers31,9341
Non-polymers4822
Water2,594144
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)95.545, 95.545, 80.060
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 Serine/threonine-protein kinase pim-1 / PIM-1 kinase


Mass: 31934.223 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 123-399)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIM-1, PIM1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-1OB / 5-(4-cyanobenzyl)-N-(4-fluorophenyl)-7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 387.367 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H14FN5O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 144 / 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: 3.3 Å3/Da / Density % sol: 62.76 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: PEG4000, 0.2 M lithium sulfate, 0.1 M Tris-HCl, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 289K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 7, 2008
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. obs: 26122 / % possible obs: 99.9 % / Redundancy: 7.1 % / Biso Wilson estimate: 41 Å2 / Rmerge(I) obs: 0.059 / Χ2: 1.032 / Net I/σ(I): 15.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.05-2.127.10.45825980.9231100
2.12-2.217.20.34925921.0031100
2.21-2.317.10.24826031.0861100
2.31-2.437.20.19125931.07199.9
2.43-2.587.20.14526201.0561100
2.58-2.787.20.10325951.0331100
2.78-3.067.30.07226021.0231100
3.06-3.517.20.05726091.0021100
3.51-4.426.90.0526391.0891100
4.42-507.10.04526711.033199.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXdev_1334refinement
PDB_EXTRACT3.11data extraction
CBASSdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.051→41.372 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8433 / SU ML: 0.19 / σ(F): 1.34 / Phase error: 23.1 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2197 1327 5.09 %
Rwork0.1841 --
obs0.1859 26089 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 155.14 Å2 / Biso mean: 47.4195 Å2 / Biso min: 24.66 Å2
Refinement stepCycle: LAST / Resolution: 2.051→41.372 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2253 0 34 144 2431
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042349
X-RAY DIFFRACTIONf_angle_d0.9163191
X-RAY DIFFRACTIONf_chiral_restr0.062336
X-RAY DIFFRACTIONf_plane_restr0.004415
X-RAY DIFFRACTIONf_dihedral_angle_d13.961858
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 9 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.051-2.13260.27451440.216827122856
2.1326-2.22970.26591550.206527622917
2.2297-2.34720.23221490.199927242873
2.3472-2.49420.26231420.203627542896
2.4942-2.68680.27721320.218927412873
2.6868-2.95710.25521550.206527592914
2.9571-3.38480.22831560.199727382894
3.3848-4.26390.19431400.167327702910
4.2639-41.38060.19221540.16528022956

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