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- PDB-2f4j: Structure of the Kinase Domain of an Imatinib-Resistant Abl Mutan... -

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Basic information

Entry
Database: PDB / ID: 2f4j
TitleStructure of the Kinase Domain of an Imatinib-Resistant Abl Mutant in Complex with the Aurora Kinase Inhibitor VX-680
ComponentsProto-oncogene tyrosine-protein kinase ABL1
KeywordsTRANSFERASE / kinase / kinase inhibitor / abl
Function / homology
Function and homology information


mitochondrial depolarization / positive regulation of actin filament binding / transitional one stage B cell differentiation / DNA conformation change / negative regulation of phospholipase C activity / regulation of extracellular matrix organization / activation of protein kinase C activity / positive regulation of interleukin-2 production => GO:0032743 / nicotinate-nucleotide adenylyltransferase activity / positive regulation blood vessel branching ...mitochondrial depolarization / positive regulation of actin filament binding / transitional one stage B cell differentiation / DNA conformation change / negative regulation of phospholipase C activity / regulation of extracellular matrix organization / activation of protein kinase C activity / positive regulation of interleukin-2 production => GO:0032743 / nicotinate-nucleotide adenylyltransferase activity / positive regulation blood vessel branching / alpha-beta T cell differentiation / B cell proliferation involved in immune response / regulation of modification of synaptic structure / positive regulation of microtubule binding / positive regulation of Wnt signaling pathway, planar cell polarity pathway / microspike assembly / neuroepithelial cell differentiation / cerebellum morphogenesis / collateral sprouting / B-1 B cell homeostasis / actin filament branching / circulatory system development => GO:0072359 / positive regulation of oxidoreductase activity / activated T cell proliferation / neuropilin binding / neuropilin signaling pathway / bubble DNA binding / regulation of Cdc42 protein signal transduction / negative regulation of protein serine/threonine kinase activity / regulation of T cell differentiation / negative regulation of ubiquitin-protein transferase activity / regulation of microtubule polymerization / negative regulation of BMP signaling pathway / regulation of actin cytoskeleton reorganization / mitogen-activated protein kinase binding / proline-rich region binding / sequence-specific double-stranded DNA binding / syntaxin binding / cellular response to dopamine / positive regulation of interferon-gamma production => GO:0032729 / negative regulation of cell-cell adhesion / DNA damage induced protein phosphorylation / negative regulation of cellular senescence / positive regulation of osteoblast proliferation / regulation of response to DNA damage stimulus / regulation of axon extension / platelet-derived growth factor receptor-beta signaling pathway / positive regulation of cell migration involved in sprouting angiogenesis / cell leading edge / negative regulation of long-term synaptic potentiation / actin monomer binding / Bergmann glial cell differentiation / regulation of endocytosis / neuromuscular process controlling balance / positive regulation of focal adhesion assembly / positive regulation of actin cytoskeleton reorganization / positive regulation of substrate adhesion-dependent cell spreading / mismatch repair / regulation of hematopoietic stem cell differentiation / negative regulation of mitotic cell cycle / negative regulation of endothelial cell apoptotic process / regulation of cell adhesion / regulation of cell motility / endothelial cell migration / four-way junction DNA binding / positive regulation of stress fiber assembly / positive regulation of muscle cell differentiation / regulation of actin cytoskeleton organization / signal transduction in response to DNA damage / substrate adhesion-dependent cell spreading / positive regulation of endothelial cell migration / regulation of autophagy / cellular protein modification process / post-embryonic development / spleen development / SH2 domain binding / negative regulation of I-kappaB kinase/NF-kappaB signaling / positive regulation of mitotic cell cycle / positive regulation of release of sequestered calcium ion into cytosol / thymus development / negative regulation of ERK1 and ERK2 cascade / protein kinase C binding / phosphotyrosine residue binding / ephrin receptor binding / integrin-mediated signaling pathway / neural tube closure / peptidyl-tyrosine autophosphorylation / actin cytoskeleton organization / non-specific protein-tyrosine kinase / establishment of protein localization / non-membrane spanning protein tyrosine kinase activity / epidermal growth factor receptor signaling pathway / autophagy / SH3 domain binding / postsynapse / cell cycle arrest / cellular response to hydrogen peroxide / positive regulation of neuron death / intrinsic apoptotic signaling pathway in response to DNA damage / B cell receptor signaling pathway
Tyrosine-protein kinase, active site / SH3-like domain superfamily / F-actin binding / Protein kinase, ATP binding site / Tyrosine-protein kinase, catalytic domain / Tyrosine-protein kinase ABL1/transforming protein Abl / Serine-threonine/tyrosine-protein kinase, catalytic domain / SH2 domain / Tyrosine-protein kinase ABL, SH2 domain / Protein kinase-like domain superfamily ...Tyrosine-protein kinase, active site / SH3-like domain superfamily / F-actin binding / Protein kinase, ATP binding site / Tyrosine-protein kinase, catalytic domain / Tyrosine-protein kinase ABL1/transforming protein Abl / Serine-threonine/tyrosine-protein kinase, catalytic domain / SH2 domain / Tyrosine-protein kinase ABL, SH2 domain / Protein kinase-like domain superfamily / SH3 domain / Protein kinase domain / SH2 domain superfamily / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
gb:62362414: / Tyrosine-protein kinase ABL1
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.91 Å
AuthorsYoung, M.A. / Shah, N.P. / Chao, L.H. / Zarrinkar, P. / Sawyers, P. / Kuriyan, J.
CitationJournal: Cancer Res. / Year: 2006
Title: Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680.
Authors: Young, M.A. / Shah, N.P. / Chao, L.H. / Seeliger, M. / Milanov, Z.V. / Biggs, W.H. / Treiber, D.K. / Patel, H.K. / Zarrinkar, P.P. / Lockhart, D.J. / Sawyers, C.L. / Kuriyan, J.
Validation Report
SummaryFull reportAbout validation report
History
DepositionNov 23, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 24, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6372
Polymers33,1721
Non-polymers4651
Water3,801211
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
γ
α
β
Length a, b, c (Å)44.768, 59.417, 66.896
Angle α, β, γ (deg.)90.00, 98.42, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Proto-oncogene tyrosine-protein kinase ABL1 / p150 / c- ABL


Mass: 33171.938 Da / Num. of mol.: 1 / Fragment: Kinase domain, residues 227-513 / Mutation: H396P
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1, ABL, JTK7 / Plasmid: pET28a-TEV / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-star
References: GenBank: 62362414, UniProt: P00519*PLUS, EC: 2.7.1.112
#2: Chemical ChemComp-VX6 / CYCLOPROPANECARBOXYLIC ACID {4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE / Tozasertib


Mass: 464.586 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28N8OS / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 211 / 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: 2.65 Å3/Da / Density % sol: 53.67 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 3.5
Details: 25% w/v PEG1500, 0.1M citric acid, pH 3.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 26, 2004
RadiationMonochromator: Double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 24731 / % possible obs: 90.4 % / Rmerge(I) obs: 0.121 / Χ2: 1.036
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2% possible all
1.9-1.970.52915261.00556.1
1.97-2.050.44619761.01672.9
2.05-2.140.38722911.03284.1
2.14-2.250.34925371.06493.2
2.25-2.390.30326581.05297.7
2.39-2.580.23727211.04799.8
2.58-2.840.17727251.048100
2.84-3.250.11627521.0499.9
3.25-4.090.08127341.03799.8
4.09-500.05528110.98899.9

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
CNS1.1refinement
PDB_EXTRACT1.701data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1M52
Resolution: 1.91→44.29 Å / Rfactor Rfree error: 0.006 / Occupancy max: 1 / Occupancy min: 1 / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: Cross-validation method: -> "throughout" Free R value test set selection criteria: -> "random"
RfactorNum. reflection% reflectionSelection details
Rfree0.239 1612 6.9 %RANDOM
Rwork0.207 ---
All0.207 27297 --
Obs0.207 23335 85.5 %-
Solvent computationSolvent model: CNS bulk solvent model used / Bsol: 47.7103 Å2 / ksol: 0.391374 e/Å3
Displacement parametersBiso max: 77.63 Å2 / Biso mean: 25.8 Å2 / Biso min: 10.41 Å2
Baniso -1Baniso -2Baniso -3
1-12.14 Å20 Å2-1.55 Å2
2---8.84 Å20 Å2
3----3.3 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.28 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.29 Å0.25 Å
Luzzati d res high-1.91
Refinement stepCycle: LAST / Resolution: 1.91→44.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2328 0 33 211 2572
Refine LS restraints
Refinement-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d21.7
X-RAY DIFFRACTIONc_improper_angle_d0.69
LS refinement shell

Refinement-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection Rfree% reflection Rfree (%)Rfactor RworkNum. reflection RworkRfactor Rfree errorNum. reflection allNum. reflection obs% reflection obs (%)
1.91-1.990.3658750.29416380.0393399172550.8
1.99-2.10.2951556.60.24821920.0243394234769.2
2.1-2.230.2942057.20.24826270.0213404283283.2
2.23-2.40.2992227.30.24428160.023404303889.2
2.4-2.640.262397.40.21529890.0173397322895
2.64-3.020.2682206.70.21630740.0183402329496.8
3.02-3.810.2232246.60.19131610.0153425338598.8
3.81-44.290.2282607.50.20932260.0143505348699.4
Xplor file
Refinement-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2vx680.parcarbohydrate.top
X-RAY DIFFRACTION3ion.param
X-RAY DIFFRACTION4water_rep.param

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