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- PDB-4ybj: Type II Dasatinib Analog Crystallized with c-Src Kinase -

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Basic information

Entry
Database: PDB / ID: 4ybj
TitleType II Dasatinib Analog Crystallized with c-Src Kinase
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE / Protein kinase / inactive conformation
Function / homology
Function and homology information


Signaling by ERBB2 / Nuclear signaling by ERBB4 / PIP3 activates AKT signaling / Signaling by SCF-KIT / Regulation of KIT signaling / Signaling by EGFR / GAB1 signalosome / Regulation of gap junction activity / FCGR activation / PECAM1 interactions ...Signaling by ERBB2 / Nuclear signaling by ERBB4 / PIP3 activates AKT signaling / Signaling by SCF-KIT / Regulation of KIT signaling / Signaling by EGFR / GAB1 signalosome / Regulation of gap junction activity / FCGR activation / PECAM1 interactions / CD28 co-stimulation / CTLA4 inhibitory signaling / EPHA-mediated growth cone collapse / Ephrin signaling / G alpha (i) signalling events / GP1b-IX-V activation signalling / Recycling pathway of L1 / Thrombin signalling through proteinase activated receptors (PARs) / VEGFR2 mediated cell proliferation / RAF activation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RET signaling / Receptor Mediated Mitophagy / ADP signalling through P2Y purinoceptor 1 / Downregulation of ERBB4 signaling / EPH-ephrin mediated repulsion of cells / Cyclin D associated events in G1 / Regulation of RUNX3 expression and activity / Activated NTRK3 signals through PI3K / Downstream signal transduction / MAP2K and MAPK activation / Integrin signaling / GRB2:SOS provides linkage to MAPK signaling for Integrins / MET activates PTK2 signaling / Extra-nuclear estrogen signaling / EPHB-mediated forward signaling / p130Cas linkage to MAPK signaling for integrins / VEGFA-VEGFR2 Pathway / connexin binding / osteoclast development / progesterone receptor signaling pathway / negative regulation of intrinsic apoptotic signaling pathway / bone resorption / extrinsic component of cytoplasmic side of plasma membrane / negative regulation of extrinsic apoptotic signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / epidermal growth factor receptor signaling pathway / cell junction / protein phosphatase binding / protein tyrosine kinase activity / mitochondrial inner membrane / cell differentiation / cytoskeleton / endosome membrane / regulation of cell cycle / cell adhesion / cell cycle / phosphorylation / signaling receptor binding / focal adhesion / innate immune response / heme binding / perinuclear region of cytoplasm / protein-containing complex / ATP binding / membrane / nucleus / plasma membrane / cytosol
Similarity search - Function
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 ...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-4A9 / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsKwarcinski, F.E. / Brandvold, K.B. / Johnson, T.K. / Phadke, S. / Meagher, J.L. / Seeliger, M.A. / Stuckey, J.A. / Soellner, M.B.
CitationJournal: Acs Chem.Biol. / Year: 2016
Title: Conformation-Selective Analogues of Dasatinib Reveal Insight into Kinase Inhibitor Binding and Selectivity.
Authors: Kwarcinski, F.E. / Brandvold, K.R. / Phadke, S. / Beleh, O.M. / Johnson, T.K. / Meagher, J.L. / Seeliger, M.A. / Stuckey, J.A. / Soellner, M.B.
History
DepositionFeb 18, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2016Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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 Src
B: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,7074
Polymers65,4532
Non-polymers1,2532
Water1,15364
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.117, 120.062, 63.319
Angle α, β, γ (deg.)90.000, 90.260, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Proto-oncogene tyrosine-protein kinase Src / / Proto-oncogene c-Src / pp60c-src / p60-Src


Mass: 32726.645 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC / Plasmid: pET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-4A9 / 2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-N-(3-{[3-(trifluoromethyl)benzoyl]amino}phenyl)-1,3-thiazole-5-carboxamide


Mass: 626.653 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H29F3N8O3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 64 / 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: 2.45 Å3/Da / Density % sol: 49.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 M MES, pH 6.5, 20% PEG 3350, 370 mM NaOAc

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.979 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 15, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.61→50 Å / Num. obs: 19186 / % possible obs: 99.9 % / Redundancy: 7.6 % / Biso Wilson estimate: 45.22 Å2 / Rmerge(I) obs: 0.074 / Χ2: 0.94 / Net I/av σ(I): 20.265 / Net I/σ(I): 12.3 / Num. measured all: 145715
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.61-2.667.30.4149491.24299.9
2.66-2.77.40.339271.23499.6
2.7-2.767.40.2849641.19199.8
2.76-2.817.40.2749821.19799.8
2.81-2.877.50.2329101.21599.8
2.87-2.947.50.1999701.17999.8
2.94-3.017.50.1729851.156100
3.01-3.097.60.1479401.097100
3.09-3.197.60.1219701.044100
3.19-3.297.70.1049440.959100
3.29-3.417.80.0899400.962100
3.41-3.547.70.0819790.957100
3.54-3.77.80.0759340.961100
3.7-3.97.70.0689740.918100
3.9-4.147.80.0619590.834100
4.14-4.467.70.0559570.75100
4.46-4.917.70.0429670.546100
4.91-5.627.70.0429690.564100
5.62-7.087.70.0389850.518100
7.08-507.40.0289810.37499.8

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Processing

Software
NameVersionClassification
BUSTER-TNTBUSTER 2.10.0refinement
HKL-2000data collection
HKL-2000data scaling
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2oiq

2oiq


Resolution: 2.61→43.56 Å / Cor.coef. Fo:Fc: 0.8975 / Cor.coef. Fo:Fc free: 0.8744 / SU R Cruickshank DPI: 0.72 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.606 / SU Rfree Blow DPI: 0.29 / SU Rfree Cruickshank DPI: 0.3
RfactorNum. reflection% reflectionSelection details
Rfree0.25 1034 5.4 %RANDOM
Rwork0.2183 ---
obs0.22 19137 99.92 %-
Displacement parametersBiso max: 211.9 Å2 / Biso mean: 43.48 Å2 / Biso min: 4.22 Å2
Baniso -1Baniso -2Baniso -3
1--5.8749 Å20 Å20.8545 Å2
2--4.8198 Å20 Å2
3---1.0551 Å2
Refine analyzeLuzzati coordinate error obs: 0.378 Å
Refinement stepCycle: final / Resolution: 2.61→43.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3937 0 88 64 4089
Biso mean--45.45 22.45 -
Num. residues----508
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1853SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes83HARMONIC2
X-RAY DIFFRACTIONt_gen_planes690HARMONIC5
X-RAY DIFFRACTIONt_it4190HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion518SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4876SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4190HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg5754HARMONIC20.91
X-RAY DIFFRACTIONt_omega_torsion2.23
X-RAY DIFFRACTIONt_other_torsion2.75
LS refinement shellResolution: 2.61→2.75 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2705 167 6.06 %
Rwork0.2434 2591 -
all0.2451 2758 -
obs--99.92 %
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)
10.05590.29340.66941.39950.32481.6188-0.01670.0448-0.0926-0.02020.0482-0.0292-0.2287-0.0186-0.0315-0.1054-0.0440.0660.026-0.0398-0.05918.523-2.41293.377
20.35980.204-0.63920.7901-0.20931.6552-0.01480.03640.0803-0.02560.03840.03710.2193-0.0288-0.0236-0.1076-0.0462-0.04690.06070.032-0.07611.449-22.80261.303
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|259 - A|533 }A259 - 533
2X-RAY DIFFRACTION2{ B|259 - B|533 }B259 - 533

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