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- PDB-3jpv: Crystal structure of human proto-oncogene serine threonine kinase... -

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Basic information

Entry
Database: PDB / ID: 3jpv
TitleCrystal structure of human proto-oncogene serine threonine kinase (PIM1) in complex with a consensus peptide and a pyrrolo[2,3-a]carbazole ligand
Components
  • Peptide (PIMTIDE) ARKRRRHPSGPPTA
  • Proto-oncogene serine/threonine-protein kinase Pim-1
Keywordstransferase / transferase inhibitor / oncogene / kinase / serine-threonine / PIM1 / pyrrolo[2 / 3-a]carbazole / Structural Genomics Consortium / SGC / Alternative initiation / ATP-binding / Cell membrane / Manganese / Membrane / Metal-binding / Nucleotide-binding / Nucleus / Phosphoprotein / Proto-oncogene / Serine/threonine-protein kinase / Transferase / 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-1DR / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.35 Å
AuthorsFilippakopoulos, P. / Bullock, A.N. / Fedorov, O. / Akue-Gedu, R. / Rossignol, E. / Azzaro, S. / Bain, J. / Cohen, P. / Prudhomme, M. / Moreau, P. ...Filippakopoulos, P. / Bullock, A.N. / Fedorov, O. / Akue-Gedu, R. / Rossignol, E. / Azzaro, S. / Bain, J. / Cohen, P. / Prudhomme, M. / Moreau, P. / Amizon, F. / von Delft, F. / Arrowsmith, C.H. / Weigelt, J. / Edwards, A. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2009
Title: Synthesis, kinase inhibitory potencies, and in vitro antiproliferative evaluation of new pim kinase inhibitors.
Authors: Akue-Gedu, R. / Rossignol, E. / Azzaro, S. / Knapp, S. / Filippakopoulos, P. / Bullock, A.N. / Bain, J. / Cohen, P. / Prudhomme, M. / Anizon, F. / Moreau, P.
History
DepositionSep 4, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 27, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _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: Proto-oncogene serine/threonine-protein kinase Pim-1
B: Peptide (PIMTIDE) ARKRRRHPSGPPTA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4183
Polymers37,1832
Non-polymers2341
Water2,900161
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)97.821, 97.821, 80.743
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 Proto-oncogene serine/threonine-protein kinase Pim-1


Mass: 35590.500 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIM1 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)-R3
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Protein/peptide Peptide (PIMTIDE) ARKRRRHPSGPPTA


Mass: 1592.850 Da / Num. of mol.: 1 / Source method: obtained synthetically
#3: Chemical ChemComp-1DR / 1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde


Mass: 234.253 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H10N2O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 161 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsAUTHORS STATE THAT THE EXPRESSED PROTEIN HAS THE SEQUENCE FROM GI 33304198 WHICH DIFFERS FROM GI ...AUTHORS STATE THAT THE EXPRESSED PROTEIN HAS THE SEQUENCE FROM GI 33304198 WHICH DIFFERS FROM GI 4505811 BY A SINGLE MUTATION R250G. AUTHORS CAN NO LONGER FIND GI|33304198 ON THE DATABASES. AUTHORS ARE NOT SURE IF THIS IS DUE TO POLYMORPHISM OR NOT. AUTHORS CONFIRM BY ESI THAT THE SEQUENCE WE HAVE CORRESPONDS TO THE R250G MUTANT AND ALSO IN OUR EXPERIMENTAL DENSITY WE SEE A G AND NOT A LARGERAMINOACID.

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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 Å3/Da / Density % sol: 58.99 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.2M NaNO3 0.1M BTProp pH 8.5 20% PEG3350 10% EtGly, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jul 7, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5 Å / Relative weight: 1
ReflectionResolution: 2.35→23.577 Å / Num. all: 18404 / Num. obs: 18386 / % possible obs: 99.9 % / Redundancy: 4.6 % / Biso Wilson estimate: 43.4 Å2 / Rmerge(I) obs: 0.127 / Rsym value: 0.127 / Net I/σ(I): 10.6
Reflection shellResolution: 2.35→2.48 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.763 / Mean I/σ(I) obs: 2 / Num. unique all: 2654 / Rsym value: 0.763 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 31.83 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å23.41 Å
Translation2.5 Å23.41 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.2data scaling
PHASER2.1.2phasing
REFMACrefinement
PDB_EXTRACT3.005data extraction
CrystalCleardata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2C3I

2c3i


Resolution: 2.35→23.577 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.92 / WRfactor Rfree: 0.199 / WRfactor Rwork: 0.153 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.878 / SU B: 12.539 / SU ML: 0.137 / SU R Cruickshank DPI: 0.234 / SU Rfree: 0.202 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.234 / ESU R Free: 0.202 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.226 913 5 %RANDOM
Rwork0.173 ---
all0.176 18363 --
obs0.176 18359 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 76.57 Å2 / Biso mean: 19.441 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.58 Å20.29 Å20 Å2
2--0.58 Å20 Å2
3----0.86 Å2
Refinement stepCycle: LAST / Resolution: 2.35→23.577 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2267 0 18 161 2446
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0212349
X-RAY DIFFRACTIONr_bond_other_d0.0010.021636
X-RAY DIFFRACTIONr_angle_refined_deg1.5491.9583188
X-RAY DIFFRACTIONr_angle_other_deg0.9143.0013926
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0445278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.38422.712118
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.77915384
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.3381523
X-RAY DIFFRACTIONr_chiral_restr0.0880.2336
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212609
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02514
X-RAY DIFFRACTIONr_mcbond_it3.77931393
X-RAY DIFFRACTIONr_mcbond_other1.2233566
X-RAY DIFFRACTIONr_mcangle_it5.27452250
X-RAY DIFFRACTIONr_scbond_it8.98956
X-RAY DIFFRACTIONr_scangle_it10.07511938
LS refinement shellResolution: 2.35→2.41 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.419 52 -
Rwork0.29 1273 -
all-1325 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
15.5191.10590.23555.68711.19145.0110.0919-0.5215-0.03030.4333-0.0449-0.2123-0.09040.4285-0.04710.10810.08190.01560.2866-0.01540.16434.315650.97677.2432
22.1806-0.0460.57320.94330.10181.56060.0275-0.1422-0.24360.11790.0949-0.11140.18350.2259-0.12240.09550.03430.01890.0892-0.01030.071919.311853.60974.3653
32.69370.53870.23612.43780.44692.6338-0.05490.09510.2132-0.08050.08840.0493-0.2430.047-0.03360.04990.00820.00140.02640.00440.0198.948964.2892-4.017
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A33 - 89
2X-RAY DIFFRACTION2A90 - 199
3X-RAY DIFFRACTION3A200 - 305

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