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- PDB-2gqg: X-ray Crystal Structure of Dasatinib (BMS-354825) Bound to Activa... -

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Basic information

Entry
Database: PDB / ID: 2gqg
TitleX-ray Crystal Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain
ComponentsProto-oncogene tyrosine-protein kinase ABL1
KeywordsTRANSFERASE / Kinase
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 / SH3 domain binding / autophagy / 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
Tyrosine-protein kinase ABL1
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsKlei, H.E.
CitationJournal: CANCER RES. / Year: 2006
Title: The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants
Authors: Tokarski, J.S. / Newitt, J. / Chang, C.Y.J. / Cheng, J.D. / Wittekind, M. / Kiefer, S.E. / Kish, K. / Lee, F.Y.F. / Borzilerri, R. / Lombardo, L.J. / Xie, D. / Zhang, Y. / Klei, H.E.
Validation Report
SummaryFull reportAbout validation report
History
DepositionApr 20, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 21, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)65,5045
Polymers64,4352
Non-polymers1,0683
Water5,585310
1
A: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7062
Polymers32,2181
Non-polymers4881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7983
Polymers32,2181
Non-polymers5802
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
γ
α
β
Length a, b, c (Å)105.192, 105.192, 111.100
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-527-

HOH

21B-568-

HOH

DetailsThe biological unit is a monomer. There are 2 biological units in the asymmetric unit.

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Components

#1: Protein Proto-oncogene tyrosine-protein kinase ABL1 / p150 / c- ABL / Abelson murine leukemia viral oncogene homolog 1


Mass: 32217.738 Da / Num. of mol.: 2 / Fragment: kinase domain, residues 229-500
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1, ABL, JTK7 / Plasmid: BACULOGOLD / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-1N1 / N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE / P150 / C-ABL / Dasatinib / Dasatinib


Mass: 488.006 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H26ClN7O2S / Comment: medication*YM
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


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


Mass: 18.015 Da / Num. of mol.: 310 / 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: 2.38 Å3/Da / Density % sol: 48.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 22% w/v PEG3350, 0.2 M MgSO4, 0.1 M MES buffer, pH 6.5, vapor diffusion, hanging drop, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 30, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 25102 / % possible obs: 100 % / Redundancy: 7.5 % / Rmerge(I) obs: 0.127 / Χ2: 1.06 / Net I/σ(I): 7
Reflection shell
Resolution (Å)% possible obs (%)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID
2.4-2.491007.60.50924550.9951
2.49-2.591007.60.41824631.0461
2.59-2.71007.60.36224611.0541
2.7-2.851007.60.26924661.041
2.85-3.021007.60.21324771.0791
3.02-3.261007.60.15624811.081
3.26-3.581007.50.11625031.0831
3.58-4.11007.50.09825160.9711
4.1-5.171007.20.07825521.1181
5.17-501007.10.05227281.1351

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Phasing

Phasing MRRfactor: 0.486 / Cor.coef. Fo:Fc: 0.355 / Cor.coef. Io to Ic: 0.402
Highest resolutionLowest resolution
Rotation4 Å10 Å
Translation4 Å10 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement
PDB_EXTRACT1.701data extraction
ADSCdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→50 Å / FOM work R set: 0.812
RfactorNum. reflection
Rfree0.273 968
Rwork0.208 -
Obs-24996
Refine analyze
FreeObs
Luzzati coordinate error0.39 Å0.28 Å
Luzzati d res low-5 Å
Luzzati sigma a0.26 Å0.18 Å
Refinement stepCycle: LAST / Resolution: 2.4→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4505 0 72 310 4887
Refine LS restraints
Refinement-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d23.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.81
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.531.5
X-RAY DIFFRACTIONc_mcangle_it2.582
X-RAY DIFFRACTIONc_scbond_it3.432
X-RAY DIFFRACTIONc_scangle_it3.422.5
LS refinement shell

Refinement-ID: X-RAY DIFFRACTION / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs
2.4-2.510.2911190.22129523071
2.51-2.640.3511000.23629613061
2.64-2.810.2821220.20729333055
2.81-3.020.2741260.2129743100
3.02-3.330.2861210.21629713092
3.33-3.810.2621110.19430143125
3.81-4.80.2551330.18730413174
4.8-500.010.2641360.22331823318
Xplor file
Refinement-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.parprotein.top
X-RAY DIFFRACTION2water_rep.parwater.top
X-RAY DIFFRACTION3ion.paramion.top
X-RAY DIFFRACTION4ligand.paramligand.top

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