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- PDB-3tz8: Kinase domain of cSrc in complex with RL104 -

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Basic information

Entry
Database: PDB / ID: 3tz8
TitleKinase domain of cSrc in complex with RL104
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Type II / Allosteric / DFG-out / Drug resistance mutations / Tyrosin-protein kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / RET signaling / Receptor Mediated Mitophagy / ADP signalling through P2Y purinoceptor 1 / RAF activation / 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 / negative regulation of intrinsic apoptotic signaling pathway / progesterone receptor 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 / 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-AQM / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.7 Å
AuthorsGruetter, C. / Richters, A. / Rauh, D.
CitationJournal: To be Published
Title: Overcoming Gatekeeper Mutations in cSrc and Abl by Hybrid Compound Design
Authors: Richters, A. / Getlik, M. / Gruetter, C. / Schneider, R. / Heuckmann, J.M. / Heynck, S. / Sos, M.L. / Thomas, R.K. / Rauh, D.
History
DepositionSep 27, 2011Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 10, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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)66,8094
Polymers65,4852
Non-polymers1,3242
Water1,44180
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4052
Polymers32,7431
Non-polymers6621
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)33,4052
Polymers32,7431
Non-polymers6621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.000, 63.580, 74.510
Angle α, β, γ (deg.)79.080, 87.690, 89.880
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: 32742.711 Da / Num. of mol.: 2 / Fragment: Kinase Domain, UNP residues 251-533 / Mutation: S345C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC, v-Src sarcoma viral oncogene / Plasmid: pSKB3 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-AQM / N-(4-{[4-({[1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl]carbamoyl}amino)phenyl]amino}quinazolin-6-yl)-3-(4-methylpiperazin-1-yl)propanamide


Mass: 661.799 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C36H43N11O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / 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: 1

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Sample preparation

CrystalDensity Matthews: 2.98 Å3/Da / Density % sol: 58.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 10% PEG 20000, 15% glycerol, 100mM MES, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.977032 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jan 30, 2009 / Details: Dynamically bendable mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977032 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. all: 20806 / Num. obs: 20010 / % possible obs: 96.2 % / Observed criterion σ(I): -3 / Redundancy: 2.26 % / Biso Wilson estimate: 33.979 Å2 / Rmerge(I) obs: 0.048 / Net I/σ(I): 14.91
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique allNum. unique obsRrim(I) all% possible all
2.7-2.82.210.2910.1685.0743702188218819760.22490.3
2.8-2.90.2430.1356.484108183917820.17996.9
2.9-30.1890.1097.813689166116150.14497.2
3-40.0860.05414.2819168872584520.07196.9
4-50.0380.03322.776915312030360.04397.3
5-60.0410.03421.353013138813400.04496.5
6-100.0330.0323.843215147714320.03997
10-500.0180.0230.538204083770.02692.4

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.7 Å41.97 Å
Translation2.7 Å41.97 Å

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASER1.3.1phasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
SLS-Softwaredata collection
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3F3V

3f3v


Resolution: 2.7→41.96 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.883 / WRfactor Rfree: 0.2509 / WRfactor Rwork: 0.1944 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8142 / SU B: 22.836 / SU ML: 0.241 / SU R Cruickshank DPI: 0.8753 / SU Rfree: 0.3426 / Cross valid method: THROUGHOUT / ESU R Free: 0.337 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2583 801 4 %RANDOM
Rwork0.198 ---
obs0.2004 20008 100 %-
all-20806 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 59.23 Å2 / Biso mean: 27.968 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-1.36 Å20.16 Å2-0.36 Å2
2---0.4 Å21.13 Å2
3----1.36 Å2
Refinement stepCycle: LAST / Resolution: 2.7→41.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4195 0 98 80 4373
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0224407
X-RAY DIFFRACTIONr_angle_refined_deg1.1362.0015982
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2855520
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.66723.814194
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.52415745
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4631529
X-RAY DIFFRACTIONr_chiral_restr0.0720.2629
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.023363
X-RAY DIFFRACTIONr_nbd_refined0.1930.21978
X-RAY DIFFRACTIONr_nbtor_refined0.3050.23019
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1320.2200
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2120.238
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1280.25
X-RAY DIFFRACTIONr_mcbond_it0.4331.52697
X-RAY DIFFRACTIONr_mcangle_it0.77524223
X-RAY DIFFRACTIONr_scbond_it0.87932025
X-RAY DIFFRACTIONr_scangle_it1.5064.51759
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.342 55 -
Rwork0.269 1315 -
all-1370 -
obs--100 %

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