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- PDB-5iis: Design, synthesis and structure activity relationship of potent p... -

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Basic information

Entry
Database: PDB / ID: 5iis
TitleDesign, synthesis and structure activity relationship of potent pan-PIM kinase inhibitors derived from the pyridyl-amide scaffold
ComponentsSerine/threonine-protein kinase pim-1
KeywordsTransferase/Transferase Inhibitor / Pim1 / moloney murine leukemia / PIM447 / kinase inhibitor / 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 / positive regulation of cyclin-dependent protein serine/threonine kinase activity / ribosomal small subunit binding / 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 / positive regulation of cyclin-dependent protein serine/threonine kinase activity / ribosomal small subunit binding / 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-6CB / DI(HYDROXYETHYL)ETHER / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsBellamacina, C. / Bussiere, D. / Burger, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Design, synthesis and structure activity relationship of potent pan-PIM kinase inhibitors derived from the pyridyl carboxamide scaffold.
Authors: Nishiguchi, G.A. / Burger, M.T. / Han, W. / Lan, J. / Atallah, G. / Tamez, V. / Lindvall, M. / Bellamacina, C. / Garcia, P. / Feucht, P. / Zavorotinskaya, T. / Dai, Y. / Wong, K.
History
DepositionMar 1, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 13, 2016Group: Data collection
Revision 1.2May 4, 2016Group: Database references

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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)32,5353
Polymers32,0141
Non-polymers5212
Water3,765209
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)97.720, 97.720, 80.609
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: 32014.203 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-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#3: Chemical ChemComp-6CB / 3-amino-N-(2'-amino-6'-methyl[4,4'-bipyridin]-3-yl)-6-(2-fluorophenyl)pyridine-2-carboxamide


Mass: 414.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H19FN6O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 209 / 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: 3.47 Å3/Da / Density % sol: 64.56 % / Description: P6(5)
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.5-1.0 mM (NH4)2HPO4; 0.1 M Sodium citrate pH 5.5; 250 mM Sodium chloride

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Data collection

DiffractionAmbient temp details: cryo
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.998 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: May 2, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.998 Å / Relative weight: 1
ReflectionResolution: 2.1→84.515 Å / Num. obs: 29642 / % possible obs: 100 % / Redundancy: 7.6 % / Biso Wilson estimate: 29.1 Å2 / Rmerge(I) obs: 0.068 / Net I/av σ(I): 7.6 / Net I/σ(I): 21.3
Reflection shellResolution: 2.1→2.11 Å / Redundancy: 7.6 % / Rmerge(I) obs: 0.416 / Mean I/σ(I) obs: 4.6 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→41.784 Å / Cor.coef. Fo:Fc: 0.9539 / Cor.coef. Fo:Fc free: 0.9493 / SU R Cruickshank DPI: 0.143 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.145 / SU Rfree Blow DPI: 0.127 / SU Rfree Cruickshank DPI: 0.126
RfactorNum. reflection% reflectionSelection details
Rfree0.1934 1297 5.06 %RANDOM
Rwork0.1708 ---
obs0.1719 25621 99.96 %-
Displacement parametersBiso mean: 35.95 Å2
Baniso -1Baniso -2Baniso -3
1-0.0515 Å20 Å20 Å2
2--0.0515 Å20 Å2
3----0.103 Å2
Refinement stepCycle: 1 / Resolution: 2.1→41.784 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2223 0 38 209 2470
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012352HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.923204HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d804SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes58HARMONIC2
X-RAY DIFFRACTIONt_gen_planes384HARMONIC5
X-RAY DIFFRACTIONt_it2352HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.19
X-RAY DIFFRACTIONt_other_torsion17.05
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_contact2816SEMIHARMONIC4
LS refinement shellResolution: 2.1→2.19 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.1953 145 5.02 %
Rwork0.1649 2745 -
all0.1665 2890 -
obs--99.96 %
Refinement TLS params.Method: refined / Origin x: -8.4315 Å / Origin y: 40.3983 Å / Origin z: 0.137 Å
111213212223313233
T0 Å20 Å20 Å2-0 Å20 Å2--0 Å2
L0 °20 °20 °2-0 °20 °2--0 °2
S0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °
Refinement TLS groupSelection details: { A|* }

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