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- PDB-4mbi: Discovery of Pyrazolo[1,5a]pyrimidine-based Pim1 Inhibitors -

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Basic information

Entry
Database: PDB / ID: 4mbi
TitleDiscovery of Pyrazolo[1,5a]pyrimidine-based Pim1 Inhibitors
ComponentsSerine/threonine-protein kinase pim-1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / 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 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 cardiac muscle cell proliferation ...positive regulation of cardioblast proliferation / positive regulation of cyclin-dependent protein serine/threonine kinase 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 cardiac muscle cell proliferation / positive regulation of brown fat cell differentiation / Signaling by FLT3 fusion proteins / positive regulation of TORC1 signaling / regulation of transmembrane transporter activity / negative regulation of innate immune response / regulation of mitotic cell cycle / protein serine/threonine kinase activator activity / negative regulation of DNA-binding transcription factor activity / cellular response to type II interferon / manganese ion binding / protein autophosphorylation / Interleukin-4 and Interleukin-13 signaling / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein stabilization / protein phosphorylation / 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 / cytosol / cytoplasm
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-26K / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.3 Å
AuthorsAzevedo, R. / Fischmann, T.O.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of pyrazolo[1,5-a]pyrimidine-based Pim inhibitors: A template-based approach.
Authors: Dwyer, M.P. / Keertikar, K. / Paruch, K. / Alvarez, C. / Labroli, M. / Poker, C. / Fischmann, T.O. / Mayer-Ezell, R. / Bond, R. / Wang, Y. / Azevedo, R. / Guzi, T.J.
History
DepositionAug 19, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 18, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 30, 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_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

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase pim-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1182
Polymers33,8461
Non-polymers2711
Water2,234124
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)97.877, 97.877, 80.625
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: 33846.348 Da / Num. of mol.: 1 / Fragment: UNP residues 120-404
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIM1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 star
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-26K / N,N-dimethyl-N'-[3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]ethane-1,2-diamine


Mass: 271.321 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H17N7
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 124 / 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: 62.66 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.4
Details: 10.5% PEG 400, 0.05 M Tris-Cl pH 8.4, 0.3 M NaCl, 0.01 M DTT, 0.01M EDTA, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→29.8 Å / Num. all: 21340 / Num. obs: 17271 / % possible obs: 80.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0

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Processing

Software
NameVersionClassification
CrystalCleardata collection
AMoREphasing
REFMAC5.4.0078refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.3→29.77 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.911 / SU B: 16.363 / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.323 / ESU R Free: 0.236 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24564 1769 10.1 %RANDOM
Rwork0.21125 ---
obs0.21484 15715 89.25 %-
all-15715 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.024 Å2
Baniso -1Baniso -2Baniso -3
1-0.9 Å20.45 Å20 Å2
2--0.9 Å20 Å2
3----1.35 Å2
Refinement stepCycle: LAST / Resolution: 2.3→29.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2230 0 20 124 2374
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0212312
X-RAY DIFFRACTIONr_bond_other_d0.0010.021601
X-RAY DIFFRACTIONr_angle_refined_deg1.7051.9583138
X-RAY DIFFRACTIONr_angle_other_deg0.9633858
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8565273
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.6123.136118
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.20215381
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7281521
X-RAY DIFFRACTIONr_chiral_restr0.0940.2332
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212570
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02506
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_it0.6871.51364
X-RAY DIFFRACTIONr_mcbond_other0.151.5555
X-RAY DIFFRACTIONr_mcangle_it1.25122211
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.023948
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.1284.5927
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.386 157 -
Rwork0.334 1245 -
obs--97.63 %
Refinement TLS params.Method: refined / Origin x: 30.974 Å / Origin y: 27.403 Å / Origin z: 0.488 Å
111213212223313233
T-0.1146 Å20.0098 Å2-0.0055 Å2--0.1197 Å20.0006 Å2---0.1015 Å2
L1.4456 °2-0.2127 °2-0.2798 °2-1.4512 °2-0.1561 °2--1.4801 °2
S-0.0457 Å °-0.0698 Å °0.0504 Å °0.0637 Å °0.0513 Å °0.0192 Å °-0.0689 Å °-0.1252 Å °-0.0056 Å °

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