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- PDB-2qlq: Crystal structure of SRC kinase domain with covalent inhibitor RL3 -

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Basic information

Entry
Database: PDB / ID: 2qlq
TitleCrystal structure of SRC kinase domain with covalent inhibitor RL3
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE / Src kinase domain / drug resistance / irreversible inhibitor / kovalent inhibitor / Alternative splicing / ATP-binding / Lipoprotein / Myristate / Nucleotide-binding / Phosphorylation / 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-SR2 / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.33 Å
AuthorsMichalczyk, A. / Rode, H.B. / Gruetter, C. / Rauh, D.
CitationJournal: Bioorg.Med.Chem. / Year: 2008
Title: Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR.
Authors: Michalczyk, A. / Kluter, S. / Rode, H.B. / Simard, J.R. / Grutter, C. / Rabiller, M. / Rauh, D.
History
DepositionJul 13, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 11, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / 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_conn.pdbx_leaving_atom_flag / _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 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
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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)66,7645
Polymers65,4852
Non-polymers1,2793
Water1,78399
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5953
Polymers32,7431
Non-polymers8532
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)33,1692
Polymers32,7431
Non-polymers4261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.940, 63.530, 74.500
Angle α, β, γ (deg.)78.28, 90.37, 89.45
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Proto-oncogene tyrosine-protein kinase Src / p60-Src / c-Src / pp60c-src


Mass: 32742.711 Da / Num. of mol.: 2 / Fragment: Protein kinase domain / Mutation: S345C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC / Plasmid: pSKB3 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-SR2 / (2E)-N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide


Mass: 426.310 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C20H20BrN5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 99 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 58.55 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 16% Ethylene glycol, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5417 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Dec 13, 2006
RadiationMonochromator: Multilayer Optic (Osmic) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5417 Å / Relative weight: 1
ReflectionResolution: 2.33→72.944 Å / Num. all: 32156 / Num. obs: 29166 / % possible obs: 90.7 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.06 / Rsym value: 0.06 / Net I/σ(I): 11.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRsym value% possible all
2.33-2.463.60.4071.80.40785.9
2.46-2.613.60.292.60.2989.2
2.61-2.783.70.1973.80.19790.2
2.78-3.013.80.12660.12691.1
3.01-3.33.80.0819.30.08191.8
3.3-3.683.80.04715.80.04792.3
3.68-4.253.80.03123.30.03192.6
4.25-5.213.80.02625.50.02693.6
5.21-7.373.80.02726.30.02793.6
7.37-52.943.80.02221.20.02293.8

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Processing

Software
NameVersionClassificationNB
SCALAdata scaling
REFMACrefinement
PDB_EXTRACT2data extraction
MAR345dtbdata collection
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.33→72.93 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.88 / SU B: 6.714 / SU ML: 0.168 / Cross valid method: THROUGHOUT / ESU R: 0.312 / ESU R Free: 0.251 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26673 1463 5 %RANDOM
Rwork0.2123 ---
obs0.21508 27702 90.72 %-
all-32683 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.043 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å2-0.08 Å20.17 Å2
2---0.44 Å20.82 Å2
3---0.05 Å2
Refinement stepCycle: LAST / Resolution: 2.33→72.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3892 0 93 99 4084
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0224096
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.771.9995566
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.7035492
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.58123.873173
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.75415672
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8771525
X-RAY DIFFRACTIONr_chiral_restr0.1240.2602
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.023103
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2190.21909
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3090.22705
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1750.2171
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2420.241
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3290.27
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.961.52541
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.64223968
X-RAY DIFFRACTIONr_scbond_it2.23731877
X-RAY DIFFRACTIONr_scangle_it3.4334.51594
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.33→2.391 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.345 98 -
Rwork0.247 1900 -
obs--84.95 %

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