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- PDB-3en4: Targeted polypharmacology: crystal structure of the c-Src kinase ... -

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Basic information

Entry
Database: PDB / ID: 3en4
TitleTargeted polypharmacology: crystal structure of the c-Src kinase domain in complex with PP121, a multitargeted kinase inhibitor
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE / SRC / tyrosine / kinase / polypharmacology / inhibitor / multitarget / phosphoinositide / signaling / pyrazolopyrimidine / kinase-inhibitor complex / ATP-binding / 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 / Co-stimulation by CD28 ...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 / Co-stimulation by CD28 / Co-inhibition by CTLA4 / 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 / immune system process / negative regulation of extrinsic apoptotic signaling pathway / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / epidermal growth factor receptor signaling pathway / cell-cell junction / cell junction / protein tyrosine kinase activity / protein phosphatase binding / cell differentiation / cytoskeleton / regulation of cell cycle / cell adhesion / mitochondrial inner membrane / endosome membrane / signaling receptor binding / focal adhesion / heme binding / perinuclear region of cytoplasm / protein-containing complex / ATP binding / nucleus / membrane / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-KS1 / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.55 Å
AuthorsBlair, J.A. / Apsel, B. / Knight, Z.A. / Shokat, K.M.
CitationJournal: Nat.Chem.Biol. / Year: 2008
Title: Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.
Authors: Apsel, B. / Blair, J.A. / Gonzalez, B. / Nazif, T.M. / Feldman, M.E. / Aizenstein, B. / Hoffman, R. / Williams, R.L. / Shokat, K.M. / Knight, Z.A.
History
DepositionSep 25, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 14, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Sep 6, 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)66,0924
Polymers65,4532
Non-polymers6392
Water1086
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0462
Polymers32,7271
Non-polymers3191
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)33,0462
Polymers32,7271
Non-polymers3191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.370, 63.143, 73.938
Angle α, β, γ (deg.)100.63, 88.68, 90.40
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: 32726.645 Da / Num. of mol.: 2 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Details: Expression plasmid is pET28a modified to yield an N-terminal, tobacco etch virus (TEV) protease cleavable His6 tag
Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-KS1 / 1-cyclopentyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine


Mass: 319.364 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H17N7
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 2.97 Å3/Da / Density % sol: 58.58 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 14 mg/mL kinase, 50 mM Tris-HCl, 100 mM NaCl, 5% (v/v) glycerol mixed 1:1 with 20% (w/v) glycerol precipitant well solution, pH 8.0, vapor diffusion, hanging drop, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 1, 2007
RadiationMonochromator: KOHZU: Double Crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.55→50 Å / Num. obs: 23940 / % possible obs: 98.4 % / Redundancy: 3.8 % / Rmerge(I) obs: 0.101 / Net I/σ(I): 12.414
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.55-2.643.30.472195
2.64-2.753.70.387197.7
2.75-2.873.90.303198.2
2.87-3.023.90.228198.5
3.02-3.213.90.175198.6
3.21-3.463.90.12198.9
3.46-3.813.90.094198.9
3.81-4.363.90.074199.2
4.36-5.493.80.065199.3
5.49-5040.054199.8

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.55 Å43.4 Å
Translation2.55 Å43.4 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.006data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1YOJ, CHAIN A

1yoj


Resolution: 2.55→42.36 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.896 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 18.376 / SU ML: 0.187 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.419 / ESU R Free: 0.283 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25457 1217 5.1 %RANDOM
Rwork0.19847 ---
obs0.2013 22721 98.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.882 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å2-0.01 Å2-0.01 Å2
2--0 Å20.01 Å2
3----0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.55→42.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4040 0 48 6 4094
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0224207
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3391.9865735
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7235520
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.43723.588170
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.63615656
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0191524
X-RAY DIFFRACTIONr_chiral_restr0.0850.2627
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213209
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1980.21857
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3050.22896
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1560.2112
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1750.234
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0910.22
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.441.52617
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.86924186
X-RAY DIFFRACTIONr_scbond_it1.79331590
X-RAY DIFFRACTIONr_scangle_it2.8514.51549
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.55→2.621 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.313 89 -
Rwork0.243 1542 -
obs--89.96 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.8142-0.996-0.69764.88543.58127.74310.08060.2813-0.0501-0.8837-0.2520.3574-0.1537-0.37360.17140.44740.01880.01730.1191-0.01690.06544.3603-5.1318-15.0352
21.52880.31220.13653.76470.12240.95570.0081-0.0634-0.0028-0.27-0.03650.24140.0119-0.18940.02840.02180.0072-0.01320.10110.00870.0537-1.49432.310810.0801
32.65550.72111.35524.2551-0.02425.83090.0666-0.2476-0.21340.9887-0.0497-0.00760.79230.2534-0.01690.49080.03360.09580.1278-0.01540.07495.8811-36.413139.9621
41.9295-0.6039-0.12292.90230.08231.672-0.0351-0.01960.05960.1642-0.0307-0.1156-0.01830.17780.06580.0165-0.0273-0.00170.10670.0140.08419.633-29.206815.2976
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A248 - 342
2X-RAY DIFFRACTION2A343 - 533
3X-RAY DIFFRACTION3B248 - 342
4X-RAY DIFFRACTION4B343 - 533

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