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- PDB-3cy2: Crystal structure of human proto-oncogene serine threonine kinase... -

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Basic information

Entry
Database: PDB / ID: 3cy2
TitleCrystal structure of human proto-oncogene serine threonine kinase (PIM1) in complex with a consensus peptide and a beta carboline ligand II
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 / cellular detoxification / regulation of hematopoietic stem cell proliferation / vitamin D receptor signaling pathway / STAT5 activation downstream of FLT3 ITD mutants / ribosomal small subunit binding / transcription factor binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / positive regulation of cardiac muscle cell proliferation / positive regulation of TORC1 signaling ...positive regulation of cardioblast proliferation / cellular detoxification / regulation of hematopoietic stem cell proliferation / vitamin D receptor signaling pathway / STAT5 activation downstream of FLT3 ITD mutants / ribosomal small subunit binding / transcription factor binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / positive regulation of cardiac muscle cell proliferation / positive regulation of TORC1 signaling / Signaling by FLT3 fusion proteins / positive regulation of brown fat cell differentiation / negative regulation of innate immune response / 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 / 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 / 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-MB9 / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.01 Å
AuthorsFilippakopoulos, P. / Bullock, A. / Fedorov, O. / Huber, K. / Bracher, F. / Pike, A.C.W. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. ...Filippakopoulos, P. / Bullock, A. / Fedorov, O. / Huber, K. / Bracher, F. / Pike, A.C.W. / 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 / Category: pdbx_struct_assembly_auth_evidence
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)37,7395
Polymers37,3132
Non-polymers4263
Water3,729207
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1120 Å2
ΔGint2.7 kcal/mol
Surface area12940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.668, 98.668, 81.129
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

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Protein / Protein/peptide , 2 types, 2 molecules AB

#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

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Non-polymers , 4 types, 210 molecules

#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-MB9 / (4R)-7-chloro-9-methyl-1-oxo-1,2,4,9-tetrahydrospiro[beta-carboline-3,4'-piperidine]-4-carbonitrile


Mass: 328.796 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17ClN4O
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 207 / 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: 3.06 Å3/Da / Density % sol: 59.74 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.56 M Na succinate pH 7.0, 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: 1.54178 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Sep 14, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionRedundancy: 5.2 % / Av σ(I) over netI: 8.4 / Number: 155741 / Rmerge(I) obs: 0.075 / Rsym value: 0.075 / D res high: 1.635 Å / D res low: 32.297 Å / Num. obs: 29963 / % possible obs: 100
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
6.3632.399.310.0330.0334.9
4.496.3610010.0340.0345.2
3.674.4910010.040.045.3
3.183.6710010.0510.0515.3
2.843.1810010.0780.0785.3
2.592.8410010.1260.1265.2
2.42.5910010.1940.1945.2
2.252.410010.280.285.2
2.122.2510010.4530.4535.2
2.012.1210010.7040.7045.1
ReflectionResolution: 2.01→32.297 Å / Num. obs: 29963 / % possible obs: 100 % / Redundancy: 5.2 % / Rmerge(I) obs: 0.075 / Rsym value: 0.075 / Net I/σ(I): 8.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.01-2.125.10.7041.12225243450.704100
2.12-2.255.20.4531.72126641270.453100
2.25-2.45.20.282.72012838810.28100
2.4-2.595.20.1943.91878636030.194100
2.59-2.845.20.12661741333270.126100
2.84-3.185.30.0789.41590930210.078100
3.18-3.675.30.05113.51401826550.051100
3.67-4.495.30.0415.91194422620.04100
4.49-6.365.20.03417.9923117650.034100
6.36-32.2974.90.03316.647949770.03399.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å29.42 Å
Translation2.18 Å29.42 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.2.25data scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.005data extraction
CrystalCleardata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2C3I

2c3i


Resolution: 2.01→32.297 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.952 / SU B: 5.454 / SU ML: 0.084 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.127 / ESU R Free: 0.122 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.199 1553 5.2 %RANDOM
Rwork0.167 ---
all0.169 29927 --
obs0.169 29927 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 mean: 26.309 Å2
Baniso -1Baniso -2Baniso -3
1-0.27 Å20.13 Å20 Å2
2--0.27 Å20 Å2
3----0.4 Å2
Refinement stepCycle: LAST / Resolution: 2.01→32.297 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2266 0 28 207 2501
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0212386
X-RAY DIFFRACTIONr_bond_other_d0.0010.021674
X-RAY DIFFRACTIONr_angle_refined_deg1.3711.9613233
X-RAY DIFFRACTIONr_angle_other_deg1.6093.0014017
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3375277
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.21122.683123
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.64715399
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.2091526
X-RAY DIFFRACTIONr_chiral_restr0.0850.2340
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212625
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02520
X-RAY DIFFRACTIONr_mcbond_it2.2831393
X-RAY DIFFRACTIONr_mcbond_other0.7123566
X-RAY DIFFRACTIONr_mcangle_it3.38252258
X-RAY DIFFRACTIONr_scbond_it5.668993
X-RAY DIFFRACTIONr_scangle_it7.6911975
LS refinement shellResolution: 2.01→2.062 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.372 114 -
Rwork0.278 2096 -
all-2210 -
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)
18.9961-0.95281.6377.02791.52836.802-0.0432-0.3664-0.32560.81980.06520.38630.9173-0.4977-0.0220.1114-0.1897-0.03840.15120.0307-0.011-23.25531.0185.913
21.50160.8437-0.40461.3242-0.39912.95870.147-0.1414-0.08340.095-0.04260.22430.4611-0.4561-0.1044-0.0348-0.0812-0.03840.05360.0054-0.0266-17.11837.6225.512
30.61650.0457-0.04531.3525-0.25271.60080.0346-0.0160.0076-0.0250.0351-0.05750.06060.0361-0.0697-0.07690-0.0266-0.0472-0.0104-0.0591-1.05945.041-1.192
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA33 - 8134 - 82
2X-RAY DIFFRACTION2AA84 - 14085 - 141
3X-RAY DIFFRACTION3AA141 - 305142 - 306

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