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- PDB-6vrv: Discovery of SARxxxx92, a pan-PIM kinase inhibitor, efficacious i... -

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Basic information

Entry
Database: PDB / ID: 6vrv
TitleDiscovery of SARxxxx92, a pan-PIM kinase inhibitor, efficacious in a KG1 tumor model
ComponentsSerine/threonine-protein kinase pim-1
KeywordsONCOPROTEIN / TRANSFERASE/INHIBITOR / inhibitor complex / 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 / 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
Similarity search - Domain/homology
Chem-WFY / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.74 Å
AuthorsBarberis, C.E. / Batchelor, J.D. / Liu, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Discovery of SARxxxx92, a pan-PIM kinase inhibitor, efficacious in a KG1 tumor model.
Authors: Barberis, C. / Erdman, P. / Czekaj, M. / Fire, L. / Pribish, J. / Tserlin, E. / Maniar, S. / Batchelor, J.D. / Liu, J. / Patel, V.F. / Hebert, A. / Levit, M. / Wang, A. / Sun, F. / Huang, S.A.
History
DepositionFeb 10, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 4, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)32,0223
Polymers31,6051
Non-polymers4172
Water4,396244
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area260 Å2
ΔGint-0 kcal/mol
Surface area12900 Å2
Unit cell
Length a, b, c (Å)98.804, 98.804, 81.187
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65

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Components

#1: Protein Serine/threonine-protein kinase pim-1


Mass: 31604.873 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-WFY / 4-chloro-1-{(1S)-1-[(3S)-3-fluoropyrrolidin-3-yl]ethyl}-3-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxamide


Mass: 324.781 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H18ClFN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 244 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.62 Å3/Da / Density % sol: 66.02 %
Crystal growTemperature: 292 K / Method: vapor diffusion / Details: 100 mM imidazole, 1.4M sodium acetate pH 6.4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97856 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Jul 25, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 1.74→86 Å / Num. obs: 46226 / % possible obs: 99.9 % / Redundancy: 7.6 % / Rmerge(I) obs: 0.109 / Net I/σ(I): 16.8
Reflection shellResolution: 1.74→1.8 Å / Rmerge(I) obs: 0.586 / Num. unique obs: 4611

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
PDB_EXTRACT3.25data extraction
d*TREKdata reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1XQZ

1xqz


Resolution: 1.74→85.57 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.954 / SU B: 2.915 / SU ML: 0.048 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.082 / ESU R Free: 0.083
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.1966 2342 5.1 %RANDOM
Rwork0.1723 ---
obs0.1735 43862 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 98.52 Å2 / Biso mean: 32.44 Å2 / Biso min: 14.68 Å2
Baniso -1Baniso -2Baniso -3
1-0.34 Å20.17 Å20 Å2
2--0.34 Å20 Å2
3----0.51 Å2
Refinement stepCycle: final / Resolution: 1.74→85.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2209 0 28 244 2481
Biso mean--28.67 41.28 -
Num. residues----271
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0320.022297
X-RAY DIFFRACTIONr_angle_refined_deg2.6721.9633120
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.625270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.76523.136118
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.80515378
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.7791521
X-RAY DIFFRACTIONr_chiral_restr0.2370.2331
X-RAY DIFFRACTIONr_gen_planes_refined0.0150.0211780
LS refinement shellResolution: 1.74→1.785 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.281 152 -
Rwork0.248 3168 -
all-3320 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 31.461 Å / Origin y: 27.523 Å / Origin z: 0.356 Å
111213212223313233
T0.0327 Å20.0165 Å2-0.0084 Å2-0.0326 Å20.0135 Å2--0.0169 Å2
L0.7978 °2-0.0821 °2-0.126 °2-0.5407 °20.0077 °2--0.6374 °2
S-0.0133 Å °-0.0229 Å °0.0118 Å °-0.0273 Å °0.0235 Å °0.0499 Å °-0.0168 Å °-0.0486 Å °-0.0102 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A35 - 305
2X-RAY DIFFRACTION1A402

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