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- PDB-4mxo: human Src kinase bound to kinase inhibitor bosutinib -

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Basic information

Entry
Database: PDB / ID: 4mxo
Titlehuman Src kinase bound to kinase inhibitor bosutinib
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Phosphorylation / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of non-membrane spanning protein tyrosine kinase activity / primary ovarian follicle growth / regulation of caveolin-mediated endocytosis / regulation of toll-like receptor 3 signaling pathway / positive regulation of ovarian follicle development / positive regulation of platelet-derived growth factor receptor-beta signaling pathway / cellular response to prolactin / positive regulation of male germ cell proliferation / dendritic filopodium / regulation of cell projection assembly ...positive regulation of non-membrane spanning protein tyrosine kinase activity / primary ovarian follicle growth / regulation of caveolin-mediated endocytosis / regulation of toll-like receptor 3 signaling pathway / positive regulation of ovarian follicle development / positive regulation of platelet-derived growth factor receptor-beta signaling pathway / cellular response to prolactin / positive regulation of male germ cell proliferation / dendritic filopodium / regulation of cell projection assembly / response to mineralocorticoid / positive regulation of dephosphorylation / ERBB2 signaling pathway / Regulation of commissural axon pathfinding by SLIT and ROBO / regulation of epithelial cell migration / positive regulation of protein transport / Regulation of gap junction activity / BMP receptor binding / positive regulation of lamellipodium morphogenesis / cellular response to progesterone stimulus / regulation of vascular permeability / positive regulation of protein processing / positive regulation of integrin activation / Activated NTRK2 signals through FYN / negative regulation of focal adhesion assembly / skeletal muscle cell proliferation / : / Netrin mediated repulsion signals / regulation of intracellular estrogen receptor signaling pathway / intestinal epithelial cell development / CD28 co-stimulation / positive regulation of glucose metabolic process / transcytosis / osteoclast development / Activated NTRK3 signals through PI3K / connexin binding / cellular response to fluid shear stress / response to acidic pH / focal adhesion assembly / signal complex assembly / positive regulation of small GTPase mediated signal transduction / positive regulation of Ras protein signal transduction / odontogenesis / positive regulation of podosome assembly / regulation of bone resorption / Regulation of RUNX1 Expression and Activity / branching involved in mammary gland duct morphogenesis / adherens junction organization / DCC mediated attractive signaling / EPH-Ephrin signaling / myoblast proliferation / Ephrin signaling / cellular response to peptide hormone stimulus / negative regulation of mitochondrial depolarization / podosome / Signal regulatory protein family interactions / cellular response to fatty acid / MET activates PTK2 signaling / Fc-gamma receptor signaling pathway involved in phagocytosis / regulation of early endosome to late endosome transport / Regulation of KIT signaling / postsynaptic specialization, intracellular component / Signaling by ALK / leukocyte migration / GP1b-IX-V activation signalling / CTLA4 inhibitory signaling / oogenesis / phospholipase activator activity / p130Cas linkage to MAPK signaling for integrins / Receptor Mediated Mitophagy / interleukin-6-mediated signaling pathway / DNA biosynthetic process / EPHA-mediated growth cone collapse / positive regulation of Notch signaling pathway / Signaling by EGFR / stress fiber assembly / positive regulation of epithelial cell migration / positive regulation of smooth muscle cell migration / stimulatory C-type lectin receptor signaling pathway / cellular response to platelet-derived growth factor stimulus / regulation of cell-cell adhesion / dendritic growth cone / regulation of heart rate by cardiac conduction / RUNX2 regulates osteoblast differentiation / Recycling pathway of L1 / PECAM1 interactions / uterus development / GRB2:SOS provides linkage to MAPK signaling for Integrins / phospholipase binding / neurotrophin TRK receptor signaling pathway / negative regulation of telomere maintenance via telomerase / RHOU GTPase cycle / platelet-derived growth factor receptor signaling pathway / Long-term potentiation / negative regulation of anoikis / FCGR activation / RET signaling / EPH-ephrin mediated repulsion of cells / ephrin receptor signaling pathway / positive regulation of bone resorption
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 / 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 / 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 / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.105 Å
AuthorsLevinson, N.M. / Boxer, S.G.
CitationJournal: Nat.Chem.Biol. / Year: 2014
Title: A conserved water-mediated hydrogen bond network defines bosutinib's kinase selectivity.
Authors: Levinson, N.M. / Boxer, S.G.
History
DepositionSep 26, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 4, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2014Group: 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: Proto-oncogene tyrosine-protein kinase Src
B: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,4824
Polymers65,4212
Non-polymers1,0612
Water5,116284
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,2412
Polymers32,7111
Non-polymers5301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,2412
Polymers32,7111
Non-polymers5301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.870, 63.185, 73.665
Angle α, β, γ (deg.)79.53, 89.31, 90.05
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 32710.582 Da / Num. of mol.: 2 / Fragment: Kinase domain, UNP residues 254-536
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SRC, SRC1 / Production host: Escherichia coli (E. coli)
References: UniProt: P12931, 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


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


Mass: 18.015 Da / Num. of mol.: 284 / 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: 2

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Sample preparation

CrystalDensity Matthews: 2.93 Å3/Da / Density % sol: 58.01 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0-4% PEG 3350, 0.2M ammonium acetate, 0.1M Hepes pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.9198 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 1, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9198 Å / Relative weight: 1
ReflectionResolution: 2.1→72.5 Å / Num. all: 43136 / Num. obs: 41368 / % possible obs: 95.9 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.2 % / Rmerge(I) obs: 0.145 / Net I/σ(I): 5.8
Reflection shellResolution: 2.1→2.21 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.539 / Mean I/σ(I) obs: 2.1 / Num. unique all: 5874 / % possible all: 93.8

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
PHENIX(phenix.refine: 1.7_650)refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.105→24.912 Å / SU ML: 0.29 / σ(F): 1.97 / Phase error: 24.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2537 2039 4.94 %random
Rwork0.2103 ---
obs0.2124 41303 96.13 %-
all-42966 --
Solvent computationShrinkage radii: 0.61 Å / VDW probe radii: 0.9 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 48.003 Å2 / ksol: 0.41 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--1.5227 Å2-0.9632 Å2-0.2362 Å2
2---2.762 Å23.7973 Å2
3---4.2848 Å2
Refinement stepCycle: LAST / Resolution: 2.105→24.912 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4270 0 72 284 4626
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084452
X-RAY DIFFRACTIONf_angle_d1.086035
X-RAY DIFFRACTIONf_dihedral_angle_d18.7151693
X-RAY DIFFRACTIONf_chiral_restr0.07640
X-RAY DIFFRACTIONf_plane_restr0.005767
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.105-2.15350.291140.24542500X-RAY DIFFRACTION94
2.1535-2.20740.28971570.24062665X-RAY DIFFRACTION97
2.2074-2.2670.30561440.23972612X-RAY DIFFRACTION97
2.267-2.33370.27011480.23552646X-RAY DIFFRACTION96
2.3337-2.40890.24951050.21742473X-RAY DIFFRACTION92
2.4089-2.49490.23781400.2112657X-RAY DIFFRACTION97
2.4949-2.59470.25771410.21692697X-RAY DIFFRACTION99
2.5947-2.71270.30151520.22232637X-RAY DIFFRACTION97
2.7127-2.85550.25691350.22012593X-RAY DIFFRACTION96
2.8555-3.03410.25271300.20672601X-RAY DIFFRACTION94
3.0341-3.26790.25441310.20662654X-RAY DIFFRACTION98
3.2679-3.59590.24171390.19692655X-RAY DIFFRACTION97
3.5959-4.11420.23721340.1832556X-RAY DIFFRACTION94
4.1142-5.17590.23091280.18382728X-RAY DIFFRACTION99
5.1759-24.9120.24641410.23912590X-RAY DIFFRACTION95

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