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- PDB-4mxy: Src M314L T338M double mutant bound to kinase inhibitor bosutinib -

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Basic information

Entry
Database: PDB / ID: 4mxy
TitleSrc M314L T338M double mutant 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


primary ovarian follicle growth / regulation of caveolin-mediated endocytosis / regulation of toll-like receptor 3 signaling pathway / regulation of cell projection assembly / 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 / negative regulation of telomere maintenance ...primary ovarian follicle growth / regulation of caveolin-mediated endocytosis / regulation of toll-like receptor 3 signaling pathway / regulation of cell projection assembly / 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 / negative regulation of telomere maintenance / positive regulation of dephosphorylation / response to mineralocorticoid / Regulation of commissural axon pathfinding by SLIT and ROBO / ERBB2 signaling pathway / regulation of epithelial cell migration / positive regulation of protein transport / Regulation of gap junction activity / cellular response to progesterone stimulus / BMP receptor binding / negative regulation of focal adhesion assembly / positive regulation of protein processing / skeletal muscle cell proliferation / positive regulation of integrin activation / Activated NTRK2 signals through FYN / regulation of vascular permeability / Netrin mediated repulsion signals / regulation of intracellular estrogen receptor signaling pathway / intestinal epithelial cell development / negative regulation of neutrophil activation / Co-stimulation by CD28 / positive regulation of glucose metabolic process / osteoclast development / transcytosis / cellular response to fluid shear stress / Activated NTRK3 signals through PI3K / connexin binding / focal adhesion assembly / signal complex assembly / response to acidic pH / adherens junction organization / positive regulation of small GTPase mediated signal transduction / branching involved in mammary gland duct morphogenesis / Regulation of RUNX1 Expression and Activity / positive regulation of Ras protein signal transduction / positive regulation of podosome assembly / DCC mediated attractive signaling / EPH-Ephrin signaling / positive regulation of lamellipodium morphogenesis / regulation of bone resorption / Ephrin signaling / myoblast proliferation / Signal regulatory protein family interactions / negative regulation of mitochondrial depolarization / cellular response to peptide hormone stimulus / odontogenesis / podosome / MET activates PTK2 signaling / cellular response to fatty acid / postsynaptic specialization, intracellular component / Regulation of KIT signaling / leukocyte migration / regulation of early endosome to late endosome transport / Signaling by ALK / GP1b-IX-V activation signalling / phospholipase activator activity / Co-inhibition by CTLA4 / oogenesis / Receptor Mediated Mitophagy / EPHA-mediated growth cone collapse / DNA biosynthetic process / interleukin-6-mediated signaling pathway / Signaling by EGFR / p130Cas linkage to MAPK signaling for integrins / positive regulation of smooth muscle cell migration / positive regulation of Notch signaling pathway / stress fiber assembly / stimulatory C-type lectin receptor signaling pathway / regulation of cell-cell adhesion / RUNX2 regulates osteoblast differentiation / negative regulation of intrinsic apoptotic signaling pathway / regulation of heart rate by cardiac conduction / uterus development / Fc-gamma receptor signaling pathway involved in phagocytosis / Recycling pathway of L1 / phospholipase binding / PECAM1 interactions / neurotrophin TRK receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / protein tyrosine kinase activator activity / dendritic growth cone / RHOU GTPase cycle / platelet-derived growth factor receptor signaling pathway / negative regulation of anoikis / RET signaling / Long-term potentiation / FCGR activation / positive regulation of epithelial cell migration / ephrin receptor signaling pathway / EPH-ephrin mediated repulsion of cells / GAB1 signalosome
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 / 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-DB8 / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.582 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 25, 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)66,5064
Polymers65,4452
Non-polymers1,0612
Water1,18966
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,2532
Polymers32,7231
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)33,2532
Polymers32,7231
Non-polymers5301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.869, 63.047, 73.956
Angle α, β, γ (deg.)79.03, 87.82, 89.91
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: 32722.637 Da / Num. of mol.: 2 / Fragment: Kinase domain, UNP residues 254-536 / Mutation: M314L T338M
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.: 66 / 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: 57.97 %
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: 1.007 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 3, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.007 Å / Relative weight: 1
ReflectionResolution: 2.582→72.7 Å / Num. all: 22899 / Num. obs: 21938 / % possible obs: 95.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.2 % / Rmerge(I) obs: 0.195 / Net I/σ(I): 4.4
Reflection shellResolution: 2.582→2.74 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.475 / Mean I/σ(I) obs: 2.1 / Num. unique all: 3164 / % possible all: 94.2

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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: 2.582→61.894 Å / SU ML: 0.35 / σ(F): 1.97 / Phase error: 26.18 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2655 1107 5.05 %imported from structure of wildtype src used as molecular replacement search model
Rwork0.2079 ---
obs0.2109 21929 94.13 %-
all-23296 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 30.988 Å2 / ksol: 0.394 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--2.4068 Å2-0.9842 Å2-0.2223 Å2
2---7.8552 Å25.0364 Å2
3---10.2621 Å2
Refinement stepCycle: LAST / Resolution: 2.582→61.894 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4272 0 72 66 4410
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084454
X-RAY DIFFRACTIONf_angle_d1.1316037
X-RAY DIFFRACTIONf_dihedral_angle_d19.4461695
X-RAY DIFFRACTIONf_chiral_restr0.074640
X-RAY DIFFRACTIONf_plane_restr0.008765
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.582-2.70.28231220.24242236X-RAY DIFFRACTION81
2.7-2.84230.3281470.22822653X-RAY DIFFRACTION96
2.8423-3.02040.27191170.22522670X-RAY DIFFRACTION96
3.0204-3.25360.29591500.21932633X-RAY DIFFRACTION96
3.2536-3.5810.26751380.20662646X-RAY DIFFRACTION96
3.581-4.09910.27071290.19442670X-RAY DIFFRACTION96
4.0991-5.1640.22361520.17532679X-RAY DIFFRACTION97
5.164-61.8940.25961520.22642635X-RAY DIFFRACTION96

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