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- PDB-4xh6: Crystal structure of proto-oncogene kinase Pim1 bound to hispidulin -

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Basic information

Entry
Database: PDB / ID: 4xh6
TitleCrystal structure of proto-oncogene kinase Pim1 bound to hispidulin
ComponentsSerine/threonine-protein kinase pim-1
KeywordsTransferase/Transferase Inhibitor / Pim1 / Hispidulin / inhibitor / kinase / Transferase-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-HUL / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.04 Å
AuthorsSu, M.-Y. / Chang, C.-I.
CitationJournal: J.Nat.Prod. / Year: 2015
Title: Total Synthesis of Hispidulin and the Structural Basis for Its Inhibition of Proto-oncogene Kinase Pim-1
Authors: Chao, S.-W. / Su, M.-Y. / Chiou, L.-C. / Chen, L.-C. / Chang, C.-I. / Huang, W.-J.
History
DepositionJan 5, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Aug 26, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2015Group: Database references
Revision 1.2Feb 5, 2020Group: Data collection / Derived calculations / Category: diffrn_source / pdbx_struct_oper_list
Item: _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Nov 8, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)34,2642
Polymers33,9641
Non-polymers3001
Water1,17165
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12940 Å2
Unit cell
Length a, b, c (Å)97.999, 97.999, 80.599
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 / Proto-oncogene serine/threonine-protein kinase Pim-1


Mass: 33963.516 Da / Num. of mol.: 1 / Fragment: UNP residues 29-313
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIM1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-HUL / 5,7-dihydroxy-2-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-one / Hispidulin


Mass: 300.263 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H12O6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 65 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsThe residue numbers correspond to the residue numbers of Isoform 2 (P11309-2).

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.38 Å3/Da / Density % sol: 63.61 % / Description: rod-like crystals
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.1 / Details: 1M NaOAc, 0.1M Imidazole / PH range: 6.5-7.1

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 0.9 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Nov 22, 2014
RadiationMonochromator: Main beamline optics is a double-crystal monochromator and a horizontal focusing mirror.
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.04→50 Å / Num. obs: 28099 / % possible obs: 100 % / Redundancy: 5.7 % / Biso Wilson estimate: 23.37 Å2 / Rmerge(I) obs: 0.068 / Net I/av σ(I): 25.066 / Net I/σ(I): 9.7
Reflection shellResolution: 2.04→2.11 Å / Redundancy: 5.7 % / Mean I/σ(I) obs: 2.1 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
Coot0.7.2model building
HKL-2000data processing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2O3P

2o3p


Resolution: 2.04→42.435 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.93 / Cross valid method: THROUGHOUT / ESU R: 0.159 / ESU R Free: 0.143 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22574 1344 5 %RANDOM
Rwork0.20026 ---
obs0.20152 25569 95.83 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.325 Å2
Baniso -1Baniso -2Baniso -3
1-0.26 Å20.13 Å20 Å2
2--0.26 Å20 Å2
3----0.85 Å2
Refinement stepCycle: LAST / Resolution: 2.04→42.435 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2224 0 22 65 2311
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0192308
X-RAY DIFFRACTIONr_bond_other_d00.022155
X-RAY DIFFRACTIONr_angle_refined_deg1.3461.963135
X-RAY DIFFRACTIONr_angle_other_deg3.54334945
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5195272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.83423.136118
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.53915380
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7521521
X-RAY DIFFRACTIONr_chiral_restr0.0960.2331
X-RAY DIFFRACTIONr_gen_planes_refined0.0150.0212600
X-RAY DIFFRACTIONr_gen_planes_other0.0260.02566
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_it1.7822.9981091
X-RAY DIFFRACTIONr_mcbond_other1.7782.9971090
X-RAY DIFFRACTIONr_mcangle_it2.9024.4851362
X-RAY DIFFRACTIONr_mcangle_other2.9024.4871363
X-RAY DIFFRACTIONr_scbond_it2.1113.2571217
X-RAY DIFFRACTIONr_scbond_other2.113.2581218
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.5034.7941774
X-RAY DIFFRACTIONr_long_range_B_refined5.23125.4972718
X-RAY DIFFRACTIONr_long_range_B_other5.23125.5052719
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.04→2.093 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.239 62 -
Rwork0.239 1142 -
obs--58.39 %

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