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- PDB-2hyy: Human Abl kinase domain in complex with imatinib (STI571, Glivec) -

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Basic information

Entry
Database: PDB / ID: 2hyy
TitleHuman Abl kinase domain in complex with imatinib (STI571, Glivec)
ComponentsProto-oncogene tyrosine-protein kinase ABL1
KeywordsTRANSFERASE / Tyrosine kinase
Function / homology
Function and homology information


: / positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / DN4 thymocyte differentiation / response to epinephrine / activation of protein kinase C activity / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process ...: / positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / DN4 thymocyte differentiation / response to epinephrine / activation of protein kinase C activity / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process / delta-catenin binding / Role of ABL in ROBO-SLIT signaling / transitional one stage B cell differentiation / regulation of postsynaptic specialization assembly / regulation of modification of synaptic structure / nicotinate-nucleotide adenylyltransferase activity / cerebellum morphogenesis / neuroepithelial cell differentiation / B cell proliferation involved in immune response / positive regulation of extracellular matrix organization / positive regulation of Wnt signaling pathway, planar cell polarity pathway / microspike assembly / B-1 B cell homeostasis / neuropilin signaling pathway / neuropilin binding / bubble DNA binding / regulation of cell motility / mitochondrial depolarization / positive regulation of establishment of T cell polarity / activated T cell proliferation / cellular response to dopamine / positive regulation of blood vessel branching / proline-rich region binding / negative regulation of mitotic cell cycle / regulation of Cdc42 protein signal transduction / mitogen-activated protein kinase binding / regulation of hematopoietic stem cell differentiation / syntaxin binding / alpha-beta T cell differentiation / positive regulation of dendrite development / positive regulation of cell migration involved in sprouting angiogenesis / peptidyl-tyrosine autophosphorylation / regulation of axon extension / positive regulation of peptidyl-tyrosine phosphorylation / regulation of T cell differentiation / negative regulation of cell-cell adhesion / HDR through Single Strand Annealing (SSA) / neuromuscular process controlling balance / Myogenesis / positive regulation of osteoblast proliferation / positive regulation of vasoconstriction / platelet-derived growth factor receptor-beta signaling pathway / RUNX2 regulates osteoblast differentiation / Fc-gamma receptor signaling pathway involved in phagocytosis / vascular endothelial cell response to oscillatory fluid shear stress / regulation of endocytosis / Bergmann glial cell differentiation / regulation of microtubule polymerization / myoblast proliferation / associative learning / negative regulation of long-term synaptic potentiation / negative regulation of cellular senescence / actin monomer binding / signal transduction in response to DNA damage / positive regulation of focal adhesion assembly / canonical NF-kappaB signal transduction / negative regulation of BMP signaling pathway / RHO GTPases Activate WASPs and WAVEs / cardiac muscle cell proliferation / ephrin receptor signaling pathway / positive regulation of T cell migration / endothelial cell migration / BMP signaling pathway / negative regulation of double-strand break repair via homologous recombination / cellular response to transforming growth factor beta stimulus / negative regulation of endothelial cell apoptotic process / mismatch repair / regulation of cell adhesion / four-way junction DNA binding / ephrin receptor binding / spleen development / positive regulation of stress fiber assembly / ruffle / ERK1 and ERK2 cascade / actin filament polymerization / phosphotyrosine residue binding / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of interleukin-2 production / positive regulation of endothelial cell migration / SH2 domain binding / substrate adhesion-dependent cell spreading / positive regulation of mitotic cell cycle / protein kinase C binding / response to endoplasmic reticulum stress / peptidyl-tyrosine phosphorylation / positive regulation of release of sequestered calcium ion into cytosol / thymus development / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / integrin-mediated signaling pathway / post-embryonic development
Similarity search - Function
F-actin binding / F-actin binding / F-actin binding domain (FABD) / Tyrosine-protein kinase ABL, SH2 domain / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain ...F-actin binding / F-actin binding / F-actin binding domain (FABD) / Tyrosine-protein kinase ABL, SH2 domain / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-STI / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsCowan-Jacob, S.W. / Fendrich, G. / Liebetanz, J. / Fabbro, D. / Manley, P.
CitationJournal: ACTA CRYSTALLOGR.,SECT.D / Year: 2007
Title: Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia.
Authors: Cowan-Jacob, S.W. / Fendrich, G. / Floersheimer, A. / Furet, P. / Liebetanz, J. / Rummel, G. / Rheinberger, P. / Centeleghe, M. / Fabbro, D. / Manley, P.W.
History
DepositionAug 8, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 16, 2007Provider: 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
Revision 1.4Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / diffrn_source / pdbx_initial_refinement_model / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_source.pdbx_synchrotron_site / _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 tyrosine-protein kinase ABL1
B: Proto-oncogene tyrosine-protein kinase ABL1
C: Proto-oncogene tyrosine-protein kinase ABL1
D: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,6888
Polymers126,7134
Non-polymers1,9744
Water3,603200
1
A: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1722
Polymers31,6781
Non-polymers4941
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)32,1722
Polymers31,6781
Non-polymers4941
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1722
Polymers31,6781
Non-polymers4941
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1722
Polymers31,6781
Non-polymers4941
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)141.679, 148.575, 115.217
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 31678.283 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-STI / 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE / STI-571 / IMATINIB


Mass: 493.603 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C29H31N7O / Comment: medication*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 200 / 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: 2.39 Å3/Da / Density % sol: 48.57 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 16 % PEG 8000, 1M MES pH 6.75, 0.2 M MgAcetate, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: EMBL/DESY, HAMBURG / Beamline: BW7B / Wavelength: 0.8452 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Jun 25, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8452 Å / Relative weight: 1
ReflectionResolution: 2.4→25 Å / Num. obs: 47532 / % possible obs: 99.5 % / Rmerge(I) obs: 0.055 / Χ2: 0.396 / Net I/σ(I): 7.3
Reflection shellResolution: 2.4→2.49 Å / Rmerge(I) obs: 0.438 / Num. unique all: 4717 / Χ2: 0.323 / % possible all: 100

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Phasing

Phasing MRRfactor: 0.424 / Cor.coef. Fo:Fc: 0.548
Highest resolutionLowest resolution
Rotation3.5 Å24.99 Å
Translation3.5 Å24.99 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT2data extraction
MAR345data collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB Entry: 2HZ0

2hz0


Resolution: 2.4→25 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.906 / SU B: 7.905 / SU ML: 0.191 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.459 / ESU R Free: 0.287 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.267 2408 5.1 %RANDOM
Rwork0.204 ---
all0.208 ---
obs-47530 99.46 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 41.042 Å2
Baniso -1Baniso -2Baniso -3
1--1.7 Å20 Å20 Å2
2--0.2 Å20 Å2
3---1.5 Å2
Refinement stepCycle: LAST / Resolution: 2.4→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8354 0 148 200 8702
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0228736
X-RAY DIFFRACTIONr_angle_refined_deg1.8581.96911865
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.22351045
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.12824.063379
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.046151404
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8961535
X-RAY DIFFRACTIONr_chiral_restr0.120.21275
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.026637
X-RAY DIFFRACTIONr_nbd_refined0.2220.24115
X-RAY DIFFRACTIONr_nbtor_refined0.3160.25875
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1770.2398
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1810.246
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4570.24
X-RAY DIFFRACTIONr_mcbond_it1.2841.55417
X-RAY DIFFRACTIONr_mcangle_it2.10828407
X-RAY DIFFRACTIONr_scbond_it2.85233979
X-RAY DIFFRACTIONr_scangle_it4.1794.53458
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.331 188 -
Rwork0.237 3273 -
obs-3461 100 %

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