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- PDB-8jn9: Crystal structure of c-Src in complex with covalent inhibitor LW-... -

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Basic information

Entry
Database: PDB / ID: 8jn9
TitleCrystal structure of c-Src in complex with covalent inhibitor LW-Srci-8
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsONCOPROTEIN/INHIBITOR / Src kinase / covalent inhibitor / auto-phosphorylation site / ONCOPROTEIN-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 / 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: 2.724 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 LW-Srci-8
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 1.1Oct 9, 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:
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Assembly

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


Theoretical massNumber of molelcules
Total (without water)60,3352
Polymers59,9871
Non-polymers3481
Water905
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 area21970 Å2
Unit cell
Length a, b, c (Å)51.012, 83.110, 106.861
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-UJ0 / N-[(1R)-1-[3,5-bis(fluoranyl)phenyl]-2-(cyclopentylamino)-2-oxidanylidene-ethyl]-N-cyclopropyl-prop-2-enamide


Mass: 348.387 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22F2N2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / 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: 34.86 %
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: BL17B / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.72→65.6 Å / Num. obs: 12417 / % possible obs: 97.5 % / Redundancy: 7 % / CC1/2: 0.997 / Net I/σ(I): 12.1
Reflection shellResolution: 2.72→2.87 Å / Num. unique obs: 1827 / CC1/2: 0.763

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.724→46.036 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 29.29 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2785 621 5.02 %
Rwork0.1986 --
obs0.2026 12368 97.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.724→46.036 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3603 0 25 5 3633
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0123718
X-RAY DIFFRACTIONf_angle_d1.3325045
X-RAY DIFFRACTIONf_dihedral_angle_d8.1592213
X-RAY DIFFRACTIONf_chiral_restr0.065545
X-RAY DIFFRACTIONf_plane_restr0.008648
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7243-2.99850.37911310.2742975X-RAY DIFFRACTION100
2.9985-3.43220.32261820.23442934X-RAY DIFFRACTION100
3.4322-4.32370.27761480.18672697X-RAY DIFFRACTION90
4.3237-46.0360.23771600.17613141X-RAY DIFFRACTION100

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