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- PDB-8jn8: Crystal structure of c-Src in complex with covalent inhibitor DC-... -

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Basic information

Entry
Database: PDB / ID: 8jn8
TitleCrystal structure of c-Src in complex with covalent inhibitor DC-Srci-6668
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsONCOPROTEIN/INHIBITOR / Src kinase / covalent inhibitor / auto-phosphorylation site / ONCOPROTEIN / ONCOPROTEIN-INHIBITOR complex
Function / homology
Function and homology information


regulation of caveolin-mediated endocytosis / positive regulation of dephosphorylation / regulation of toll-like receptor 3 signaling pathway / cellular response to progesterone stimulus / Regulation of commissural axon pathfinding by SLIT and ROBO / regulation of epithelial cell migration / negative regulation of telomere maintenance / Regulation of gap junction activity / ERBB2 signaling pathway / positive regulation of integrin activation ...regulation of caveolin-mediated endocytosis / positive regulation of dephosphorylation / regulation of toll-like receptor 3 signaling pathway / cellular response to progesterone stimulus / Regulation of commissural axon pathfinding by SLIT and ROBO / regulation of epithelial cell migration / negative regulation of telomere maintenance / Regulation of gap junction activity / ERBB2 signaling pathway / positive regulation of integrin activation / BMP receptor binding / negative regulation of focal adhesion assembly / Activated NTRK2 signals through FYN / intestinal epithelial cell development / focal adhesion assembly / Netrin mediated repulsion signals / negative regulation of neutrophil activation / bone resorption / positive regulation of small GTPase mediated signal transduction / connexin binding / Activated NTRK3 signals through PI3K / signal complex assembly / regulation of vascular permeability / Co-stimulation by CD28 / EPH-Ephrin signaling / podosome / positive regulation of lamellipodium morphogenesis / DCC mediated attractive signaling / regulation of bone resorption / Regulation of RUNX1 Expression and Activity / stress fiber assembly / Ephrin signaling / Signal regulatory protein family interactions / negative regulation of mitochondrial depolarization / leukocyte migration / MET activates PTK2 signaling / Regulation of KIT signaling / cellular response to peptide hormone stimulus / regulation of early endosome to late endosome transport / Signaling by ALK / phospholipase activator activity / GP1b-IX-V activation signalling / Co-inhibition by CTLA4 / EPHA-mediated growth cone collapse / p130Cas linkage to MAPK signaling for integrins / interleukin-6-mediated signaling pathway / positive regulation of Notch signaling pathway / positive regulation of Rac protein signal transduction / stimulatory C-type lectin receptor signaling pathway / Receptor Mediated Mitophagy / Signaling by EGFR / negative regulation of intrinsic apoptotic signaling pathway / RUNX2 regulates osteoblast differentiation / Fc-gamma receptor signaling pathway involved in phagocytosis / PECAM1 interactions / regulation of cell-cell adhesion / GRB2:SOS provides linkage to MAPK signaling for Integrins / progesterone receptor signaling pathway / RHOU GTPase cycle / Recycling pathway of L1 / positive regulation of epithelial cell migration / RET signaling / regulation of heart rate by cardiac conduction / FCGR activation / signaling receptor activator activity / negative regulation of anoikis / Long-term potentiation / EPH-ephrin mediated repulsion of cells / vascular endothelial growth factor receptor signaling pathway / ephrin receptor signaling pathway / transforming growth factor beta receptor signaling pathway / GAB1 signalosome / negative regulation of hippo signaling / protein tyrosine kinase activator activity / T cell costimulation / Nuclear signaling by ERBB4 / lactation / osteoclast differentiation / negative regulation of protein-containing complex assembly / ephrin receptor binding / phospholipase binding / Signaling by ERBB2 / Integrin signaling / p38MAPK events / EPHB-mediated forward signaling / positive regulation of TORC1 signaling / peptidyl-tyrosine phosphorylation / NCAM signaling for neurite out-growth / Downstream signal transduction / FCGR3A-mediated IL10 synthesis / ionotropic glutamate receptor binding / positive regulation of glycolytic process / SH2 domain binding / integrin-mediated signaling pathway / response to interleukin-1 / negative regulation of extrinsic apoptotic signaling pathway / Downregulation of ERBB4 signaling / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / InlA-mediated entry of Listeria monocytogenes into host cells / angiotensin-activated signaling pathway
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.902 Å
AuthorsZhang, H.M. / Luo, C.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: To Be Published
Title: The crystal structure of c-Src in complex with covalent inhibitor DC-Srci-6668
Authors: Zhang, H.M. / Luo, C.
History
DepositionJun 6, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,3052
Polymers59,9871
Non-polymers3181
Water6,071337
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area21480 Å2
Unit cell
Length a, b, c (Å)51.189, 82.910, 106.623
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 59986.555 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SRC, SRC1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P12931, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-JA6 / (2R)-N-cyclopentyl-2-[cyclopropyl(ethanoyl)amino]-2-(4-fluorophenyl)ethanamide


Mass: 318.386 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H23FN2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 337 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 1.89 Å3/Da / Density % sol: 34.78 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / Details: 0.2M tri-Lithium citrate, 20%(w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NFPSS / Beamline: BL19U1 / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 24, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.9→46.15 Å / Num. obs: 35546 / % possible obs: 97.63 % / Redundancy: 12.8 % / CC1/2: 0.991 / Net I/σ(I): 22.77
Reflection shellResolution: 1.9→1.97 Å / Num. unique obs: 3029 / CC1/2: 0.663

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.902→46.146 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 24.89 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2535 1732 4.87 %
Rwork0.2097 --
obs0.2118 35546 97.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.902→46.146 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3621 0 23 337 3981
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083734
X-RAY DIFFRACTIONf_angle_d0.9655063
X-RAY DIFFRACTIONf_dihedral_angle_d15.9042227
X-RAY DIFFRACTIONf_chiral_restr0.059547
X-RAY DIFFRACTIONf_plane_restr0.005649
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.902-1.95760.29851130.27172315X-RAY DIFFRACTION82
1.9576-2.02080.27361330.25182775X-RAY DIFFRACTION97
2.0208-2.0930.26151390.23672768X-RAY DIFFRACTION97
2.093-2.17680.30621280.232845X-RAY DIFFRACTION99
2.1768-2.27590.27991550.23512801X-RAY DIFFRACTION99
2.2759-2.39580.25161430.23062831X-RAY DIFFRACTION99
2.3958-2.54590.27081640.22892844X-RAY DIFFRACTION99
2.5459-2.74250.25881420.22562851X-RAY DIFFRACTION99
2.7425-3.01840.30321630.22642860X-RAY DIFFRACTION99
3.0184-3.45510.27041540.20032907X-RAY DIFFRACTION100
3.4551-4.35250.2161610.16912924X-RAY DIFFRACTION100
4.3525-46.1460.20251370.1873093X-RAY DIFFRACTION100

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