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

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Basic information

Entry
Database: PDB / ID: 3cxw
TitleCrystal structure of human proto-oncogene serine threonine kinase (PIM1) in complex with a consensus peptide and a beta carboline ligand I
Components
  • Pimtide peptide
  • Proto-oncogene serine/threonine-protein kinase Pim-1, Isoform 2
KeywordsTRANSFERASE / oncogene / kinase / serine-threonine / PIM1 / Structural Genomics Consortium / SGC / Alternative initiation / ATP-binding / Manganese / Membrane / Metal-binding / Nucleotide-binding / Nucleus / Phosphoprotein / Proto-oncogene / Serine/threonine-protein kinase / Host-virus interaction / Viral immunoevasion / Virion / Virulence
Function / homology
Function and homology information


positive regulation of cardioblast proliferation / 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 cyclin-dependent protein serine/threonine kinase activity / positive regulation of cardiac muscle cell proliferation / negative regulation of innate immune response ...positive regulation of cardioblast proliferation / 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 cyclin-dependent protein serine/threonine kinase activity / positive regulation of cardiac muscle cell proliferation / negative regulation of innate immune response / Signaling by FLT3 fusion proteins / positive regulation of brown fat cell differentiation / positive regulation of TORC1 signaling / 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 / non-specific serine/threonine protein kinase / protein stabilization / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / negative regulation of apoptotic process / nucleolus / apoptotic process / positive regulation of DNA-templated transcription / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
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 ...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-7CP / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsFilippakopoulos, P. / Bullock, A. / Fedorov, O. / Huber, K. / Bracher, F. / Pike, A.C.W. / Roos, A. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. ...Filippakopoulos, P. / Bullock, A. / Fedorov, O. / Huber, K. / Bracher, F. / Pike, A.C.W. / Roos, A. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2012
Title: 7,8-Dichloro-1-oxo-beta-carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes
Authors: Huber, K. / Brault, L. / Fedorov, O. / Gasser, C. / Filippakopoulos, P. / Bullock, A.N. / Fabbro, D. / Trappe, J. / Schwaller, J. / Knapp, S. / Bracher, F.
History
DepositionApr 25, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Jan 18, 2012Group: Database references
Revision 1.3Jun 19, 2013Group: Database references
Revision 1.4Oct 25, 2017Group: Author supporting evidence / Refinement description / Category: pdbx_struct_assembly_auth_evidence / software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.5Oct 20, 2021Group: Database references / Derived calculations / Category: 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
Revision 1.6Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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, Isoform 2
B: Pimtide peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7254
Polymers37,3132
Non-polymers4132
Water3,909217
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1140 Å2
ΔGint2.3 kcal/mol
Surface area12910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.371, 98.371, 81.332
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65
DetailsAUTHORS STATE THAT BY GEL FILTRATION THE PROTEIN APPEARS TO BE MONOMERIC. THE BIOLOGICAL ASSEMBLY SHOWN IN REMARK 350 IS A MONOMERIC COMPLEX BETWEEN THE PROTEIN AND THE CONSENSUS PEPTIDE.

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Components

#1: Protein Proto-oncogene serine/threonine-protein kinase Pim-1, Isoform 2


Mass: 35719.680 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 (E. coli) / Strain (production host): BL21(DE3)-R3
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Protein/peptide Pimtide peptide


Mass: 1592.850 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: Synthetic peptide
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-7CP / (4R)-7,8-dichloro-1',9-dimethyl-1-oxo-1,2,4,9-tetrahydrospiro[beta-carboline-3,4'-piperidine]-4-carbonitrile


Mass: 377.268 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18Cl2N4O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 217 / 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: 3.04 Å3/Da / Density % sol: 59.6 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.14 M Sodium malonate, 0.07 M Bis-Tris-Propane pH 7.5, 14 % PEG 3350, 7 % Ethylene glycol, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.97912 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 8, 2007
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97912 Å / Relative weight: 1
ReflectionRedundancy: 3.8 % / Av σ(I) over netI: 6.3 / Number: 100036 / Rmerge(I) obs: 0.126 / Χ2: 1.57 / D res high: 2.1 Å / D res low: 50 Å / Num. obs: 26203 / % possible obs: 100
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsChi squaredRedundancy
4.525099.710.0632.5513.7
3.594.5210010.0772.8513.8
3.143.5910010.0962.1163.8
2.853.1410010.1341.5083.8
2.652.8510010.1881.2463.8
2.492.6510010.2581.1473.8
2.372.4910010.3341.0733.8
2.262.3710010.4091.0683.8
2.182.2610010.5691.0813.8
2.12.1810010.7241.0353.8
ReflectionResolution: 2.1→50 Å / Num. all: 26203 / Num. obs: 26203 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Rmerge(I) obs: 0.126 / Rsym value: 0.126 / Χ2: 1.567 / Net I/σ(I): 6.3
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.724 / Num. unique all: 2592 / Χ2: 1.035 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å37.73 Å
Translation2.5 Å37.73 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.005data extraction
CrystalCleardata collection
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2C3I

2c3i


Resolution: 2.1→36.71 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.938 / SU B: 7.081 / SU ML: 0.102 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.145 / ESU R Free: 0.141 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.206 1330 5.1 %RANDOM
Rwork0.164 ---
all0.166 26168 --
obs0.166 26168 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.425 Å2
Baniso -1Baniso -2Baniso -3
1-0.12 Å20.06 Å20 Å2
2--0.12 Å20 Å2
3----0.18 Å2
Refinement stepCycle: LAST / Resolution: 2.1→36.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2263 0 26 217 2506
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0212369
X-RAY DIFFRACTIONr_bond_other_d0.0020.021639
X-RAY DIFFRACTIONr_angle_refined_deg1.4771.9613216
X-RAY DIFFRACTIONr_angle_other_deg1.6533.0013942
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4945279
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.88622.881118
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.06515389
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4881522
X-RAY DIFFRACTIONr_chiral_restr0.0890.2340
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212617
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02510
X-RAY DIFFRACTIONr_mcbond_it2.19631402
X-RAY DIFFRACTIONr_mcbond_other0.6383570
X-RAY DIFFRACTIONr_mcangle_it3.452266
X-RAY DIFFRACTIONr_scbond_it5.518967
X-RAY DIFFRACTIONr_scangle_it7.36411950
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.298 97 -
Rwork0.229 1805 -
all-1902 -
obs--99.95 %
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)
17.19911.3385-1.76028.044-0.61695.542-0.07290.65320.3287-0.65580.09990.3187-0.5789-0.4082-0.027-0.00210.13750.03650.0891-0.0066-0.058126.533655.03367.229
21.4127-0.46770.00532.0274-0.44531.94250.03990.02730.0656-0.0097-0.01050.0781-0.1242-0.1029-0.0295-0.17440.00880.0232-0.1478-0.0159-0.185244.117241.991813.7399
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA33 - 8634 - 87
2X-RAY DIFFRACTION2AA87 - 30588 - 306

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