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- PDB-3lok: Drug resistant cSrc kinase domain in complex with covalent inhibi... -

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Basic information

Entry
Database: PDB / ID: 3lok
TitleDrug resistant cSrc kinase domain in complex with covalent inhibitor PD168393
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Src kinase domain / drug resistance / irreversible inhibitor / covalent inhibitor / PD168393 / ATP-binding / Kinase / Lipoprotein / Myristate / Nucleotide-binding / Phosphoprotein / Proto-oncogene / SH2 domain / SH3 domain / Tyrosine-protein kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Signaling by ERBB2 / Nuclear signaling by ERBB4 / PIP3 activates AKT signaling / Signaling by SCF-KIT / Regulation of KIT signaling / Signaling by EGFR / GAB1 signalosome / Regulation of gap junction activity / FCGR activation / PECAM1 interactions ...Signaling by ERBB2 / Nuclear signaling by ERBB4 / PIP3 activates AKT signaling / 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 / Recycling pathway of L1 / Thrombin signalling through proteinase activated receptors (PARs) / VEGFR2 mediated cell proliferation / RAF activation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RET signaling / Receptor Mediated Mitophagy / ADP signalling through P2Y purinoceptor 1 / Downregulation of ERBB4 signaling / EPH-ephrin mediated repulsion of cells / Cyclin D associated events in G1 / Regulation of RUNX3 expression and activity / Activated NTRK3 signals through PI3K / Downstream signal transduction / MAP2K and MAPK activation / Integrin signaling / GRB2:SOS provides linkage to MAPK signaling for Integrins / MET activates PTK2 signaling / Extra-nuclear estrogen signaling / EPHB-mediated forward signaling / p130Cas linkage to MAPK signaling for integrins / VEGFA-VEGFR2 Pathway / connexin binding / osteoclast development / progesterone receptor signaling pathway / negative regulation of intrinsic apoptotic signaling pathway / bone resorption / extrinsic component of cytoplasmic side of plasma membrane / 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 phosphatase binding / protein tyrosine kinase activity / mitochondrial inner membrane / cell differentiation / cytoskeleton / endosome membrane / regulation of cell cycle / cell adhesion / cell cycle / phosphorylation / signaling receptor binding / focal adhesion / innate immune response / 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 ...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 / 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-DJK / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.48 Å
AuthorsGruetter, C. / Rode, H.B. / Rauh, D.
CitationJournal: Chembiochem / Year: 2010
Title: Characterization of irreversible kinase inhibitors by directly detecting covalent bond formation: a tool for dissecting kinase drug resistance
Authors: Klueter, S. / Simard, J.R. / Rode, H.B. / Gruetter, C. / Pawar, V. / Raaijmakers, H.C. / Barf, T.A. / Rabiller, M. / van Otterlo, W.A.L. / Rauh, D.
History
DepositionFeb 4, 2010Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Dec 22, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 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_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

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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)66,2844
Polymers65,5462
Non-polymers7382
Water1,13563
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1422
Polymers32,7731
Non-polymers3691
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)33,1422
Polymers32,7731
Non-polymers3691
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.090, 63.260, 74.220
Angle α, β, γ (deg.)78.490, 88.330, 90.000
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: 32772.801 Da / Num. of mol.: 2 / Fragment: Kinase domain / Mutation: T338M, 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-DJK / N-[4-(3-BROMO-PHENYLAMINO)-QUINAZOLIN-6-YL]-ACRYLAMIDE


Mass: 369.215 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H13BrN4O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 63 / 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: 2.95 Å3/Da / Density % sol: 58.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 18% ethylene glycol, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5417 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Nov 23, 2006 / Details: Multilayer Optic (Rigaku)
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5417 Å / Relative weight: 1
ReflectionResolution: 2.48→52.63 Å / Num. all: 26558 / Num. obs: 24859 / % possible obs: 93.6 % / Redundancy: 2.2 % / Biso Wilson estimate: 42.1 Å2 / Rmerge(I) obs: 0.095 / Rsym value: 0.095 / Net I/σ(I): 8.5
Reflection shellResolution: 2.48→2.61 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.425 / Mean I/σ(I) obs: 1.8 / Num. measured all: 7576 / Num. unique all: 3559 / Rsym value: 0.425 / % possible all: 91.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.2.5data scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.005data extraction
MAR345dtbdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2HWP

2hwp


Resolution: 2.48→52.63 Å / Cor.coef. Fo:Fc: 0.91 / Cor.coef. Fo:Fc free: 0.86 / WRfactor Rfree: 0.265 / WRfactor Rwork: 0.205 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.819 / SU B: 9.109 / SU ML: 0.208 / SU R Cruickshank DPI: 0.418 / SU Rfree: 0.305 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.418 / ESU R Free: 0.305 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.286 1268 5.1 %RANDOM
Rwork0.221 ---
obs0.225 24836 93.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 76.89 Å2 / Biso mean: 32.425 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.17 Å20.22 Å2-0.33 Å2
2---1.07 Å20.58 Å2
3---0.69 Å2
Refinement stepCycle: LAST / Resolution: 2.48→52.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3895 0 46 63 4004
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0224053
X-RAY DIFFRACTIONr_angle_refined_deg1.9321.9875496
X-RAY DIFFRACTIONr_dihedral_angle_1_deg12.6865486
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.61823.631179
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.40115686
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7261529
X-RAY DIFFRACTIONr_chiral_restr0.1250.2592
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023071
X-RAY DIFFRACTIONr_nbd_refined0.2480.22031
X-RAY DIFFRACTIONr_nbtor_refined0.3230.22724
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1920.2193
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2370.255
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3170.28
X-RAY DIFFRACTIONr_mcbond_it1.1061.52510
X-RAY DIFFRACTIONr_mcangle_it1.75923936
X-RAY DIFFRACTIONr_scbond_it2.35931832
X-RAY DIFFRACTIONr_scangle_it3.7024.51558
LS refinement shellResolution: 2.48→2.544 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.376 97 -
Rwork0.283 1684 -
all-1781 -
obs-1781 92.71 %

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