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

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Basic information

Entry
Database: PDB / ID: 4mbl
TitleDiscovery of Pyrazolo[1,5a]pyrimidine-based Pim1 Inhibitors
ComponentsSerine/threonine-protein kinase pim-1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / PIM1 / 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-26L / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.6 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 11, 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)34,2042
Polymers33,8461
Non-polymers3571
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)98.560, 98.560, 80.859
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-26L / (1R,2R)-N-[3-(naphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl]cyclohexane-1,2-diamine


Mass: 357.452 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H23N5

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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: 3.35 Å3/Da / Density % sol: 63.28 %
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 / Date: Jun 15, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→38 Å / Num. all: 13821 / Num. obs: 13800 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.3 % / Biso Wilson estimate: 56.52 Å2 / Rmerge(I) obs: 0.147 / Rsym value: 0.083 / Net I/σ(I): 13.7
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.763 / Mean I/σ(I) obs: 1.9 / Num. unique all: 1989 / Rsym value: 0.738 / % possible all: 99.9

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Processing

Software
NameVersionClassification
CrystalCleardata collection
AMoREphasing
BUSTER2.11.4refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.6→22.36 Å / Cor.coef. Fo:Fc: 0.9137 / Cor.coef. Fo:Fc free: 0.8764 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2425 1388 10.07 %RANDOM
Rwork0.2013 ---
all0.202 13778 --
obs0.2056 13778 99.97 %-
Displacement parametersBiso mean: 34.65 Å2
Baniso -1Baniso -2Baniso -3
1--3.0304 Å20 Å20 Å2
2---3.0304 Å20 Å2
3---6.0608 Å2
Refine analyzeLuzzati coordinate error obs: 0.354 Å
Refinement stepCycle: LAST / Resolution: 2.6→22.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2230 0 27 0 2257
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014496HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.068102HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d974SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes58HARMONIC2
X-RAY DIFFRACTIONt_gen_planes666HARMONIC5
X-RAY DIFFRACTIONt_it4496HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.27
X-RAY DIFFRACTIONt_other_torsion16.61
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion279SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4827SEMIHARMONIC4
LS refinement shellResolution: 2.6→2.81 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2868 285 10.17 %
Rwork0.2169 2518 -
all0.2241 2803 -
obs--99.97 %

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