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- PDB-3jya: Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent... -

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Basic information

Entry
Database: PDB / ID: 3jya
TitleDiscovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors
ComponentsProto-oncogene serine/threonine-protein kinase Pim-1
KeywordsTRANSFERASE / PIM-1 / Alternative initiation / ATP-binding / Cell membrane / Cytoplasm / Kinase / Manganese / Membrane / Metal-binding / Nucleotide-binding / Nucleus / Phosphoprotein / Polymorphism / Proto-oncogene / Serine/threonine-protein kinase
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-LWG / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsStoll, V.S.
CitationJournal: TO BE PUBLISHED
Title: Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors
Authors: Tao, Z.F. / Hasvold, L. / Leverson, J. / Han, E. / Guan, R. / Johson, E.F. / Stoll, V.S. / Stewart, K.D. / Stamper, G. / Soni, N.
History
DepositionSep 21, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 10, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)34,2352
Polymers33,9641
Non-polymers2711
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)96.764, 96.764, 80.794
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 Proto-oncogene serine/threonine-protein kinase Pim-1


Mass: 33963.516 Da / Num. of mol.: 1
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-LWG / 6,9-dichloro[1]benzothieno[3,2-d]pyrimidin-4(3H)-one


Mass: 271.123 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H4Cl2N2OS

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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: 3.21 Å3/Da / Density % sol: 61.74 %
Crystal growTemperature: 312 K / Method: vapor diffusion, hanging drop / Details: VAPOR DIFFUSION, HANGING DROP, temperature 312K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 25245 / % possible obs: 94.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2

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Processing

SoftwareName: REFMAC / Version: 5.2.0005 / Classification: refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.1→48.39 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.911 / SU B: 4.596 / SU ML: 0.125 / Cross valid method: THROUGHOUT / ESU R: 0.205 / ESU R Free: 0.176 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25723 1226 5.1 %RANDOM
Rwork0.23286 ---
obs0.23409 22706 94.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.967 Å2
Baniso -1Baniso -2Baniso -3
1-0.28 Å20.14 Å20 Å2
2--0.28 Å20 Å2
3----0.42 Å2
Refinement stepCycle: LAST / Resolution: 2.1→48.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2230 0 16 0 2246
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0212308
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2871.9573135
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.95273
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.7123.136118
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.83115381
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3161521
X-RAY DIFFRACTIONr_chiral_restr0.0940.2332
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021821
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.20.2966
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.30.21563
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1230.272
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2010.228
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1140.28
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8441.51421
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.40122211
X-RAY DIFFRACTIONr_scbond_it1.81331080
X-RAY DIFFRACTIONr_scangle_it2.8364.5924
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.303 79 -
Rwork0.282 1411 -
obs--80.5 %

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