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- PDB-8k79: Crystal structure of c-SRC kinase domain bound by TPX-0022 -

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Basic information

Entry
Database: PDB / ID: 8k79
TitleCrystal structure of c-SRC kinase domain bound by TPX-0022
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE / SRC / TPX-0022
Function / homology
Function and homology information


Signaling by ERBB2 / Nuclear signaling by ERBB4 / 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 ...Signaling by ERBB2 / Nuclear signaling by ERBB4 / 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 / Thrombin signalling through proteinase activated receptors (PARs) / VEGFR2 mediated cell proliferation / RAF activation / RET signaling / Receptor Mediated Mitophagy / ADP signalling through P2Y purinoceptor 1 / PIP3 activates AKT signaling / EPH-ephrin mediated repulsion of cells / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Activated NTRK3 signals through PI3K / Downstream signal transduction / Downregulation of ERBB4 signaling / Cyclin D associated events in G1 / Regulation of RUNX3 expression and activity / MAP2K and MAPK activation / Integrin signaling / GRB2:SOS provides linkage to MAPK signaling for Integrins / DCC mediated attractive signaling / MET activates PTK2 signaling / Extra-nuclear estrogen signaling / EPHB-mediated forward signaling / p130Cas linkage to MAPK signaling for integrins / VEGFA-VEGFR2 Pathway / connexin binding / progesterone receptor signaling pathway / negative regulation of intrinsic apoptotic signaling pathway / 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 tyrosine kinase activity / protein phosphatase binding / mitochondrial inner membrane / cell differentiation / cytoskeleton / regulation of cell cycle / cell adhesion / endosome membrane / innate immune response / signaling receptor binding / focal adhesion / 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 / 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 speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsQu, L.Z. / Chen, Y.H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Comput Struct Biotechnol J / Year: 2023
Title: Structural insight into the macrocyclic inhibitor TPX-0022 of c-Met and c-Src.
Authors: Qu, L. / Lin, H. / Dai, S. / Guo, M. / Chen, X. / Jiang, L. / Zhang, H. / Li, M. / Liang, X. / Chen, Z. / Wei, H. / Chen, Y.
History
DepositionJul 26, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)66,2724
Polymers65,4532
Non-polymers8192
Water1,51384
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1362
Polymers32,7271
Non-polymers4091
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1362
Polymers32,7271
Non-polymers4091
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.863, 63.056, 73.084
Angle α, β, γ (deg.)100.48, 91.10, 90.22
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: 32726.645 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC / Production host: Escherichia coli (E. coli)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-IYC / Elzovantinib / (11S)-16-amino-2-ethyl-6-fluoro-11-methyl-14-oxo-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaene-5-carbonitrile / TPX-0022


Mass: 409.417 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20FN7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 84 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.9 Å3/Da / Density % sol: 57.55 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 2% glycerol, 8% PEG 4000, 50mM sodium acetate, 10mM MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97915 Å
DetectorType: ADSC QUANTUM 1 / Detector: CCD / Date: May 29, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 2.33→25 Å / Num. obs: 30487 / % possible obs: 97.3 % / Redundancy: 3.2 % / CC1/2: 0.583 / Net I/σ(I): 2.6
Reflection shellResolution: 2.33→2.39 Å / Num. unique obs: 2236 / CC1/2: 0.22

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→25 Å / Cross valid method: FREE R-VALUE / σ(F): 1.89 / Phase error: 30 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflection
Rfree0.277 1163 6.46 %
Rwork0.2414 --
obs0.2485 18012 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.8→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3941 0 60 84 4085
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024107
X-RAY DIFFRACTIONf_angle_d0.5825588
X-RAY DIFFRACTIONf_dihedral_angle_d5.2559
X-RAY DIFFRACTIONf_chiral_restr0.04608
X-RAY DIFFRACTIONf_plane_restr0.004713
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.930.28081430.27942099X-RAY DIFFRACTION94
2.93-3.080.30451460.25422098X-RAY DIFFRACTION93
3.08-3.270.26611450.23622126X-RAY DIFFRACTION94
3.27-3.530.24171400.23782123X-RAY DIFFRACTION94
3.53-3.880.35171430.30722095X-RAY DIFFRACTION93
3.88-4.440.24151430.20432086X-RAY DIFFRACTION93
4.44-5.580.2831500.2142111X-RAY DIFFRACTION93
5.58-250.2731410.2412123X-RAY DIFFRACTION94

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