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- PDB-3ue4: Structural and spectroscopic analysis of the kinase inhibitor bos... -

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Basic information

Entry
Database: PDB / ID: 3ue4
TitleStructural and spectroscopic analysis of the kinase inhibitor bosutinib binding to the Abl tyrosine kinase domain
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Protein Kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


: / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / transitional one stage B cell differentiation / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process / DN4 thymocyte differentiation / Role of ABL in ROBO-SLIT signaling / response to epinephrine ...: / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / transitional one stage B cell differentiation / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process / DN4 thymocyte differentiation / Role of ABL in ROBO-SLIT signaling / response to epinephrine / activation of protein kinase C activity / nicotinate-nucleotide adenylyltransferase activity / regulation of modification of synaptic structure / positive regulation of microtubule binding / delta-catenin binding / B cell proliferation involved in immune response / positive regulation of extracellular matrix organization / neuroepithelial cell differentiation / microspike assembly / positive regulation of Wnt signaling pathway, planar cell polarity pathway / cerebellum morphogenesis / positive regulation of blood vessel branching / B-1 B cell homeostasis / mitochondrial depolarization / negative regulation of ubiquitin-protein transferase activity / neuropilin signaling pathway / neuropilin binding / bubble DNA binding / negative regulation of protein serine/threonine kinase activity / activated T cell proliferation / cellular response to dopamine / regulation of cell motility / regulation of Cdc42 protein signal transduction / proline-rich region binding / positive regulation of dendrite development / mitogen-activated protein kinase binding / myoblast proliferation / alpha-beta T cell differentiation / regulation of hematopoietic stem cell differentiation / syntaxin binding / cardiac muscle cell proliferation / regulation of T cell differentiation / regulation of axon extension / HDR through Single Strand Annealing (SSA) / positive regulation of cell migration involved in sprouting angiogenesis / Fc-gamma receptor signaling pathway involved in phagocytosis / negative regulation of cell-cell adhesion / Myogenesis / regulation of microtubule polymerization / positive regulation of osteoblast proliferation / RUNX2 regulates osteoblast differentiation / platelet-derived growth factor receptor-beta signaling pathway / positive regulation of focal adhesion assembly / negative regulation of cellular senescence / Bergmann glial cell differentiation / associative learning / neuromuscular process controlling balance / regulation of endocytosis / negative regulation of BMP signaling pathway / negative regulation of mitotic cell cycle / actin monomer binding / negative regulation of long-term synaptic potentiation / negative regulation of double-strand break repair via homologous recombination / endothelial cell migration / RHO GTPases Activate WASPs and WAVEs / mismatch repair / positive regulation of T cell migration / canonical NF-kappaB signal transduction / BMP signaling pathway / negative regulation of endothelial cell apoptotic process / regulation of cell adhesion / four-way junction DNA binding / positive regulation of substrate adhesion-dependent cell spreading / signal transduction in response to DNA damage / peptidyl-tyrosine autophosphorylation / positive regulation of vasoconstriction / positive regulation of stress fiber assembly / spleen development / ERK1 and ERK2 cascade / ruffle / cellular response to transforming growth factor beta stimulus / positive regulation of establishment of T cell polarity / positive regulation of interleukin-2 production / actin filament polymerization / phosphotyrosine residue binding / response to endoplasmic reticulum stress / SH2 domain binding / ephrin receptor binding / positive regulation of mitotic cell cycle / substrate adhesion-dependent cell spreading / post-embryonic development / positive regulation of endothelial cell migration / positive regulation of release of sequestered calcium ion into cytosol / protein kinase C binding / thymus development / regulation of autophagy / neural tube closure / integrin-mediated signaling pathway / establishment of localization in cell / regulation of actin cytoskeleton organization
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 / Src homology 3 domains ...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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-DB8 / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.424 Å
AuthorsBoxer, S.G. / Levinson, N.M.
CitationJournal: Plos One / Year: 2012
Title: Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the abl tyrosine kinase domain.
Authors: Levinson, N.M. / Boxer, S.G.
History
DepositionOct 28, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 18, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2012Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase ABL1
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,5074
Polymers66,4462
Non-polymers1,0612
Water2,738152
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7532
Polymers33,2231
Non-polymers5301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7532
Polymers33,2231
Non-polymers5301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)56.860, 113.760, 127.640
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

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


Mass: 33222.988 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1, ABL, JTK7 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 DE3
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-DB8 / 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile / Bosutinib / Bosutinib


Mass: 530.446 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H29Cl2N5O3 / Comment: inhibitor, medication*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 152 / 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: 3.12 Å3/Da / Density % sol: 60.64 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.1M Ammonium Acetate 0.1M BisTris pH 5.5 11% PEG 10K, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.424→63.82 Å / Num. all: 19000 / Num. obs: 18506 / % possible obs: 93.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 5.9 % / Rmerge(I) obs: 0.112 / Net I/σ(I): 13.5
Reflection shellResolution: 2.424→2.56 Å / Redundancy: 6 % / Rmerge(I) obs: 0.552 / Mean I/σ(I) obs: 3.1 / Num. unique all: 4385 / % possible all: 94.8

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.7_650)refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.424→63.82 Å / SU ML: 0.37 / σ(F): 0 / Phase error: 23.46 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2487 2033 6.74 %
Rwork0.188 --
obs0.192 -93.51 %
all-19093 -
Solvent computationShrinkage radii: 0.72 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 37.279 Å2 / ksol: 0.374 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--3.0929 Å20 Å2-0 Å2
2--14.1901 Å20 Å2
3----11.0972 Å2
Refinement stepCycle: LAST / Resolution: 2.424→63.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4364 0 72 152 4588
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084551
X-RAY DIFFRACTIONf_angle_d1.0596159
X-RAY DIFFRACTIONf_dihedral_angle_d18.7491693
X-RAY DIFFRACTIONf_chiral_restr0.075648
X-RAY DIFFRACTIONf_plane_restr0.004769
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.424-2.48040.32021310.25731834X-RAY DIFFRACTION92
2.4804-2.54240.30061350.2411901X-RAY DIFFRACTION96
2.5424-2.61120.33571480.22271880X-RAY DIFFRACTION96
2.6112-2.6880.29941290.22621918X-RAY DIFFRACTION96
2.688-2.77480.28611360.21091914X-RAY DIFFRACTION97
2.7748-2.87390.29061390.19371879X-RAY DIFFRACTION96
2.8739-2.9890.22271370.18651892X-RAY DIFFRACTION95
2.989-3.1250.27451360.18361868X-RAY DIFFRACTION94
3.125-3.28980.27621280.19161827X-RAY DIFFRACTION92
3.2898-3.49590.2161340.17291815X-RAY DIFFRACTION90
3.4959-3.76580.22511340.16791800X-RAY DIFFRACTION90
3.7658-4.14470.23621300.16851803X-RAY DIFFRACTION90
4.1447-4.74430.19561360.15141872X-RAY DIFFRACTION91
4.7443-5.97660.21861330.17221904X-RAY DIFFRACTION94
5.9766-63.84210.24821470.20972018X-RAY DIFFRACTION93
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)
10.5047-0.64940.57791.1004-0.74180.8042-0.0654-0.11510.25040.0303-0.1344-0.0686-0.12770.0046-0.23490.1552-0.0558-0.05660.3537-0.17490.28719.007719.7929-40.7157
20.38020.284-0.67470.78390.67693.62430.1206-0.44190.34820.00440.01890.1786-0.351-0.93880.37230.1236-0.0446-0.02930.44640.01040.31085.910917.8621-46.6071
30.6859-0.0799-0.14371.57620.14380.37720.2192-0.18790.1596-0.0007-0.0498-0.2195-0.08480.06910.07440.146-0.05380.05710.1385-0.09770.2002-1.678123.7842-40.3064
40.37790.0816-0.03350.4844-0.0220.189-0.0484-0.12110.03-0.09870.0633-0.01390.02840.10450.02450.0558-0.0047-0.00160.1644-0.06680.1027-7.39658.1578-44.6191
50.2206-0.26560.12010.3339-0.15210.0713-0.16140.12990.15420.06790.0105-0.2109-0.04940.1874-0.05520.2223-0.05070.02530.3586-0.14110.2663-16.789419.639-33.8596
60.2737-0.09860.03040.0436-0.06810.30160.01840.0182-0.0056-0.10150.00770.0946-0.07540.1537-0.00410.1253-0.0172-0.0160.0882-0.04390.1043-23.815414.1276-47.8644
70.59910.02110.0130.50340.03350.4050.0351-0.1604-0.0753-0.10130.07460.0380.082-0.19140.05710.1058-0.0343-0.00870.09250.010.1068-27.33423.392-46.3026
80.51510.0482-0.22210.52070.09950.23680.18380.31310.2349-0.51120.0622-0.0285-0.4472-0.12370.03610.56690.16720.03210.4181-0.00880.1362-15.207346.6767-41.1119
91.01740.2776-0.96340.0757-0.26270.9115-0.09330.33690.3587-0.19910.15770.0539-0.0899-0.31330.04910.38130.0981-0.15320.2361-0.01620.3455-14.646853.3572-34.8924
100.59260.3694-0.34110.2297-0.2120.1955-0.0594-0.60940.15780.1226-0.0303-0.2308-0.48570.3372-0.00880.4550.0001-0.03060.2676-0.06080.2176-4.617250.5038-29.2736
110.29890.14680.35730.38940.05840.5765-0.07180.1502-0.0164-0.3281-0.06140.0774-0.0546-0.1535-0.01250.24230.0301-0.03640.2807-0.06360.1884-17.241539.2946-29.6233
120.56780.1649-0.18080.09970.13960.77270.17930.0780.08330.02310.018-0.0605-0.2248-0.0460.09830.15930.02520.03950.0964-0.07220.1571-9.846940.7904-16.4203
130.1738-0.1891-0.25490.24160.15280.73860.08720.0002-0.04690.0384-0.07720.00240.0187-0.142-0.00120.1455-0.04320.02290.123-0.07490.1691-16.932536.6269-4.2105
140.10320.0147-0.04850.06-0.07250.09690.05610.0997-0.2565-0.14430.0707-0.29250.35920.08170.02490.32140.0792-0.0280.1098-0.05640.2184-10.59721.9439-14.5513
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resseq 233:247)
2X-RAY DIFFRACTION2chain 'A' and (resseq 248:264)
3X-RAY DIFFRACTION3chain 'A' and (resseq 265:292)
4X-RAY DIFFRACTION4chain 'A' and (resseq 293:379)
5X-RAY DIFFRACTION5chain 'A' and (resseq 380:396)
6X-RAY DIFFRACTION6chain 'A' and (resseq 397:444)
7X-RAY DIFFRACTION7chain 'A' and (resseq 445:502)
8X-RAY DIFFRACTION8chain 'B' and (resseq 233:264)
9X-RAY DIFFRACTION9chain 'B' and (resseq 265:279)
10X-RAY DIFFRACTION10chain 'B' and (resseq 280:292)
11X-RAY DIFFRACTION11chain 'B' and (resseq 293:336)
12X-RAY DIFFRACTION12chain 'B' and (resseq 337:417)
13X-RAY DIFFRACTION13chain 'B' and (resseq 418:485)
14X-RAY DIFFRACTION14chain 'B' and (resseq 486:502)

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