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- PDB-4wrs: Crystal structure of human Pim-1 kinase in complex with an azaspi... -

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Basic information

Entry
Database: PDB / ID: 4wrs
TitleCrystal structure of human Pim-1 kinase in complex with an azaspiro pyrazinyl-indazole inhibitor.
ComponentsSerine/threonine-protein kinase pim-1
Keywordstransferase/transferase inhibitor / TRANSFERASE / serine/threonine protein kinase / transferase-transferase inhibitor complex
Function / homology
Function and homology information


positive regulation of cardioblast proliferation / positive regulation of cyclin-dependent protein serine/threonine kinase activity / regulation of transmembrane transporter activity / regulation of hematopoietic stem cell proliferation / vitamin D receptor signaling pathway / cellular detoxification / STAT5 activation downstream of FLT3 ITD mutants / transcription factor binding / ribosomal small subunit binding / positive regulation of protein serine/threonine kinase activity ...positive regulation of cardioblast proliferation / positive regulation of cyclin-dependent protein serine/threonine kinase activity / regulation of transmembrane transporter activity / regulation of hematopoietic stem cell proliferation / vitamin D receptor signaling pathway / cellular detoxification / STAT5 activation downstream of FLT3 ITD mutants / transcription factor binding / ribosomal small subunit binding / positive regulation of protein serine/threonine kinase activity / negative regulation of DNA-binding transcription factor activity / positive regulation of cardiac muscle cell proliferation / positive regulation of brown fat cell differentiation / Signaling by FLT3 fusion proteins / positive regulation of TORC1 signaling / regulation of mitotic cell cycle / negative regulation of innate immune response / protein serine/threonine kinase activator activity / cellular response to type II interferon / manganese ion binding / protein autophosphorylation / Interleukin-4 and Interleukin-13 signaling / protein phosphorylation / non-specific serine/threonine protein kinase / protein stabilization / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / nucleolus / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Serine/threonine-protein kinase pim-1/2/3 / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Serine/threonine-protein kinase pim-1/2/3 / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-3U1 / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsMohr, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: The discovery of novel 3-(pyrazin-2-yl)-1H-indazoles as potent pan-Pim kinase inhibitors.
Authors: Wang, H.L. / Cee, V.J. / Chavez, F. / Lanman, B.A. / Reed, A.B. / Wu, B. / Guerrero, N. / Lipford, J.R. / Sastri, C. / Winston, J. / Andrews, K.L. / Huang, X. / Lee, M.R. / Mohr, C. / Xu, Y. ...Authors: Wang, H.L. / Cee, V.J. / Chavez, F. / Lanman, B.A. / Reed, A.B. / Wu, B. / Guerrero, N. / Lipford, J.R. / Sastri, C. / Winston, J. / Andrews, K.L. / Huang, X. / Lee, M.R. / Mohr, C. / Xu, Y. / Zhou, Y. / Tasker, A.S.
History
DepositionOct 25, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 4, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 11, 2015Group: Database references
Revision 1.2Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_oper_list / struct_keywords
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _struct_keywords.text

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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)33,6824
Polymers33,0641
Non-polymers6183
Water2,558142
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)97.815, 97.815, 80.585
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


Mass: 33064.422 Da / Num. of mol.: 1 / Fragment: unp residues 124-396
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIM1 / Production host: Escherichia coli (E. coli)
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.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-3U1 / 3-{6-[(4R)-6-azaspiro[2.5]oct-4-yloxy]pyrazin-2-yl}-5-(2,6-difluorophenyl)-1H-indazole


Mass: 433.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H21F2N5O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 142 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.37 Å3/Da / Density % sol: 63.46 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 1.0M LiCl, 0.1M TRIS, 20% PEG6K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Jan 24, 2014
RadiationMonochromator: VariMax HF / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. obs: 22333 / % possible obs: 98.4 % / Redundancy: 11.4 % / Rmerge(I) obs: 0.083 / Net I/σ(I): 11.2
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 11.3 % / Rmerge(I) obs: 0.561 / Mean I/σ(I) obs: 4.95 / % possible all: 97

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Processing

SoftwareName: REFMAC / Version: 5.8.0049 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→29.75 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.947 / SU B: 4.215 / SU ML: 0.107 / Cross valid method: THROUGHOUT / ESU R: 0.187 / ESU R Free: 0.159
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20781 1123 5.1 %RANDOM
Rwork0.17891 ---
obs0.1804 20815 98.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 44.684 Å2
Baniso -1Baniso -2Baniso -3
1--1.81 Å2-0.91 Å20 Å2
2---1.81 Å20 Å2
3---5.88 Å2
Refinement stepCycle: 1 / Resolution: 2.2→29.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2225 0 44 142 2411
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192332
X-RAY DIFFRACTIONr_bond_other_d0.0010.022179
X-RAY DIFFRACTIONr_angle_refined_deg1.1011.973167
X-RAY DIFFRACTIONr_angle_other_deg0.71835003
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2615272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.0523.136118
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.53415380
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5311521
X-RAY DIFFRACTIONr_chiral_restr0.0680.2334
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212611
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02569
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_it1.8074.3311091
X-RAY DIFFRACTIONr_mcbond_other1.8074.3291090
X-RAY DIFFRACTIONr_mcangle_it2.9026.4871362
X-RAY DIFFRACTIONr_mcangle_other2.9026.4891363
X-RAY DIFFRACTIONr_scbond_it1.94.5991241
X-RAY DIFFRACTIONr_scbond_other1.8994.5991242
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.26.8081803
X-RAY DIFFRACTIONr_long_range_B_refined5.37734.8272706
X-RAY DIFFRACTIONr_long_range_B_other5.36334.6822665
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.201→2.258 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.265 79 -
Rwork0.228 1514 -
obs--97.07 %

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