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- PDB-4o2p: Kinase domain of cSrc in complex with a substituted pyrazolopyrimidine -

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Basic information

Entry
Database: PDB / ID: 4o2p
TitleKinase domain of cSrc in complex with a substituted pyrazolopyrimidine
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PYRAZOLO-PYRIMIDINE LIGAND / TYPE I / DFG-IN / TYROSINE PROTEIN KINASE / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


connexin binding / negative regulation of intrinsic apoptotic signaling pathway / progesterone receptor signaling pathway / immune system process / negative regulation of extrinsic apoptotic signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cell junction / epidermal growth factor receptor signaling pathway / cell-cell junction ...connexin binding / negative regulation of intrinsic apoptotic signaling pathway / progesterone receptor signaling pathway / immune system process / negative regulation of extrinsic apoptotic signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cell junction / epidermal growth factor receptor signaling pathway / cell-cell junction / protein tyrosine kinase activity / protein phosphatase binding / cytoskeleton / regulation of cell cycle / cell differentiation / cell adhesion / endosome membrane / mitochondrial inner membrane / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-11V / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsRichters, A. / Rauh, D.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Combining X-ray Crystallography and Molecular Modeling toward the Optimization of Pyrazolo[3,4-d]pyrimidines as Potent c-Src Inhibitors Active in Vivo against Neuroblastoma.
Authors: Tintori, C. / Fallacara, A.L. / Radi, M. / Zamperini, C. / Dreassi, E. / Crespan, E. / Maga, G. / Schenone, S. / Musumeci, F. / Brullo, C. / Richters, A. / Gasparrini, F. / Angelucci, A. / ...Authors: Tintori, C. / Fallacara, A.L. / Radi, M. / Zamperini, C. / Dreassi, E. / Crespan, E. / Maga, G. / Schenone, S. / Musumeci, F. / Brullo, C. / Richters, A. / Gasparrini, F. / Angelucci, A. / Festuccia, C. / Delle Monache, S. / Rauh, D. / Botta, M.
History
DepositionDec 17, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 20, 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)66,4434
Polymers65,4532
Non-polymers9902
Water4,252236
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,2222
Polymers32,7271
Non-polymers4951
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)33,2222
Polymers32,7271
Non-polymers4951
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.215, 63.248, 74.813
Angle α, β, γ (deg.)101.35, 90.44, 90.07
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 / Fragment: PROTEIN KINASE DOMAIN (UNP RESIDUES 251-533)
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-11V / 1-[(2R)-2-chloro-2-phenylethyl]-6-{[2-(morpholin-4-yl)ethyl]sulfanyl}-N-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine


Mass: 495.039 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H27ClN6OS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 236 / 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: 58.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 10% ETHYLENE GLYCOL, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9786 / Wavelength: 0.9786 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Aug 26, 2011 / Details: DYNAMIC BENDABLE MIRROR
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. all: 44252 / Num. obs: 42544 / % possible obs: 96.1 % / Observed criterion σ(I): -3 / Redundancy: 1.92 % / Biso Wilson estimate: 36.53 Å2 / Rmerge(I) obs: 0.044 / Net I/σ(I): 11.85
Reflection shell

Diffraction-ID: 1

Resolution (Å)Highest resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique all% possible all
2.1-2.21.950.2013.95549795.4
2.2-2.30.1485.0895.8
2.3-2.40.1166.3996.3
2.4-2.50.0957.896.2
2.5-2.60.0878.6496.5
2.6-2.80.079.8296.2
2.8-3.10.05213.1696.7
3.1-3.20.04615.1196.2
3.2-3.30.04116.7996.9
3.3-3.60.03519.2896.2
3.6-4.40.03122.2896.3
4.4-6.20.03122.696.4
6.2-80.03122.8995.9
8-120.0292696
12-160.02628.6292.6
160.02329.1192.2

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Processing

Software
NameVersionClassification
XDSdata scaling
PHASERphasing
REFMAC5.6.0093refinement
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2OIQ

2oiq


Resolution: 2.1→43.34 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.934 / SU B: 4.296 / SU ML: 0.112 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.186 / ESU R Free: 0.169 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2385 851 2 %RANDOM
Rwork0.1966 ---
obs0.1974 42544 96.11 %-
all-44252 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.379 Å2
Baniso -1Baniso -2Baniso -3
1--0.14 Å20.09 Å20.16 Å2
2--0.09 Å2-0.77 Å2
3----0.24 Å2
Refinement stepCycle: LAST / Resolution: 2.1→43.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4241 0 68 236 4545
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0224437
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1421.9966016
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5285530
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.81723.788198
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.19215760
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.4121531
X-RAY DIFFRACTIONr_chiral_restr0.0730.2642
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213364
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.316 61 -
Rwork0.279 3006 -
obs--94.43 %

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