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- PDB-3f3v: Kinase domain of cSrc in complex with inhibitor RL45 (Type II) -

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Basic information

Entry
Database: PDB / ID: 3f3v
TitleKinase domain of cSrc in complex with inhibitor RL45 (Type II)
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE / Allosteric / Type II / DFG-out / ATP-binding / Kinase / Lipoprotein / Myristate / Nucleotide-binding / Phosphoprotein / Proto-oncogene / SH2 domain / SH3 domain / Tyrosine-protein kinase
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-1BU / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.6 Å
AuthorsGrutter, C. / Kluter, S. / Getlik, M. / Rauh, D.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc
Authors: Getlik, M. / Grutter, C. / Simard, J.R. / Kluter, S. / Rabiller, M. / Rode, H.B. / Robubi, A. / Rauh, D.
History
DepositionOct 31, 2008Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 2, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Nov 10, 2021Group: Database references / Derived calculations / Category: 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
Revision 1.3Nov 1, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)66,4994
Polymers65,4852
Non-polymers1,0132
Water95553
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,2492
Polymers32,7431
Non-polymers5071
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)33,2492
Polymers32,7431
Non-polymers5071
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.055, 63.397, 74.955
Angle α, β, γ (deg.)79.060, 87.720, 90.080
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Proto-oncogene tyrosine-protein kinase Src / pp60c-src / p60-Src / c-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) / Plasmid: pSKB3 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-1BU / 1-{4-[(6-aminoquinazolin-4-yl)amino]phenyl}-3-[3-tert-butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea / 1-[4-(6-Amino-quinazolin-4-ylamino)-phenyl]-3-(5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl)-urea


Mass: 506.602 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H30N8O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / 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: 2.99 Å3/Da / Density % sol: 58.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 10% PEG 20000, 15% glycerol, 85 mM 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: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jul 20, 2008 / Details: Dynamically bendable mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→40 Å / Num. all: 23389 / Num. obs: 21983 / % possible obs: 94 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 38.29 Å2 / Rmerge(I) obs: 0.077 / Net I/σ(I): 13.04
Reflection shellResolution: 2.6→2.7 Å / Rmerge(I) obs: 0.221 / Mean I/σ(I) obs: 6.2 / Num. measured obs: 6793 / Num. unique all: 2324 / Num. unique obs: 2324 / % possible all: 92.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.6 Å62.24 Å
Translation2.6 Å62.24 Å

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.006data extraction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2OIQ

2oiq


Resolution: 2.6→40 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.837 / WRfactor Rfree: 0.283 / WRfactor Rwork: 0.219 / Occupancy max: 1 / Occupancy min: 0.38 / FOM work R set: 0.746 / SU B: 25.867 / SU ML: 0.268 / SU R Cruickshank DPI: 0.582 / SU Rfree: 0.334 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.576 / ESU R Free: 0.338 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.284 880 4 %RANDOM
Rwork0.21 ---
obs0.213 21983 100 %-
all-23389 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 65.35 Å2 / Biso mean: 23.622 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.89 Å2-0.34 Å20.4 Å2
2---1.09 Å20.19 Å2
3---0.09 Å2
Refinement stepCycle: LAST / Resolution: 2.6→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4143 0 76 53 4272
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0224346
X-RAY DIFFRACTIONr_angle_refined_deg1.8931.9955907
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4435523
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.20323.495186
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.60715727
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7441530
X-RAY DIFFRACTIONr_chiral_restr0.1260.2629
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023323
X-RAY DIFFRACTIONr_nbd_refined0.2450.22093
X-RAY DIFFRACTIONr_nbtor_refined0.3250.22950
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2030.2197
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.330.265
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.160.27
X-RAY DIFFRACTIONr_mcbond_it0.9271.52686
X-RAY DIFFRACTIONr_mcangle_it1.57324219
X-RAY DIFFRACTIONr_scbond_it2.27931970
X-RAY DIFFRACTIONr_scangle_it3.54.51686
LS refinement shellResolution: 2.6→2.667 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.421 65 -
Rwork0.372 1543 -
all-1608 -
obs-1543 100 %
Refinement TLS params.Method: refined / Origin x: -6.621 Å / Origin y: 14.81 Å / Origin z: 11.969 Å
111213212223313233
T-0.0569 Å20.0173 Å2-0.0064 Å2-0.0595 Å20.0102 Å2--0.0133 Å2
L0.1659 °20.1363 °2-0.0461 °2-1.7 °2-0.3416 °2--0.3064 °2
S-0.002 Å °0.0067 Å °-0.0085 Å °0.024 Å °-0.0334 Å °-0.0284 Å °-0.0297 Å °-0.0809 Å °0.0354 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A256 - 533
2X-RAY DIFFRACTION1B256 - 533

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