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- PDB-5sys: c-Src V281C bound to N-[3-({6-[(1E)-2-cyano-3-(methylamino)-3-oxo... -

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Basic information

Entry
Database: PDB / ID: 5sys
Titlec-Src V281C bound to N-[3-({6-[(1E)-2-cyano-3-(methylamino)-3-oxoprop-1-en-1-yl]-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)-4-methylphenyl]-3-(trifluoromethyl)benzamide inhibitor
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / DFG-out / covalently-linked inihibitor / 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-72F / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsDieter, E.M. / Merritt, E.A. / Maly, D.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM086858 United States
CitationJournal: Mol.Cell
Title: A combined approach reveals a regulatory mechanism coupling Src's kinase activity, localization, and phosphotransferase-independent functions
Authors: Register, A.C. / Maly, D.J.
History
DepositionAug 11, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 16, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2018Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Feb 27, 2019Group: Data collection / Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.title
Revision 1.3Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_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)66,6384
Polymers65,4612
Non-polymers1,1772
Water1,20767
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3192
Polymers32,7311
Non-polymers5891
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)33,3192
Polymers32,7311
Non-polymers5891
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.813, 63.857, 75.625
Angle α, β, γ (deg.)77.870, 90.100, 89.830
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: ASP / Beg label comp-ID: ASP / End auth comp-ID: LEU / End label comp-ID: LEU / Refine code: 0 / Auth seq-ID: 258 - 533 / Label seq-ID: 11 - 286

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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


Mass: 32730.656 Da / Num. of mol.: 2 / Mutation: V281C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC / Production host: Escherichia coli (E. coli)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-72F / N-[3-({6-[(2S)-2-cyano-3-(methylamino)-3-oxopropyl]-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)-4-methylphenyl]-3-(trifluoromethyl)benzamide / N-[3-({6-[(1E)-2-cyano-3-(methylamino)-3-oxoprop-1-en-1-yl]-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl}ethynyl)-4-methylphenyl]-3-(trifluoromethyl)benzamide inhibitor, bound form


Mass: 588.580 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H27F3N6O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 67 / 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: 3.02 Å3/Da / Density % sol: 59.21 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 100 mM MES pH 6, 8% PEG 3350, 10 mM NaOAc, 14% glycerol, 10 mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.8→73.94 Å / Num. obs: 16285 / % possible obs: 86.6 % / Redundancy: 3.3 % / CC1/2: 0.987 / Rmerge(I) obs: 0.176 / Rpim(I) all: 0.111 / Rrim(I) all: 0.209 / Net I/σ(I): 5.7 / Num. measured all: 54004 / Scaling rejects: 27
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.8-2.973.31.334859725950.4980.8331.578185.6
8.4-43.413.50.04220405910.9990.0250.04920.785

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
Aimless0.5.15data scaling
PDB_EXTRACT3.2data extraction
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3uqg

3uqg


Resolution: 2.8→73.94 Å / Cor.coef. Fo:Fc: 0.819 / Cor.coef. Fo:Fc free: 0.792 / SU B: 32.468 / SU ML: 0.544 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.527 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3339 827 5.1 %RANDOM
Rwork0.2857 ---
obs0.2881 15434 86.49 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 218.95 Å2 / Biso mean: 64.488 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1--0.61 Å20.24 Å2-0.06 Å2
2---2.41 Å21.23 Å2
3---3.25 Å2
Refinement stepCycle: final / Resolution: 2.8→73.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4128 0 86 67 4281
Biso mean--87.09 27.36 -
Num. residues----516
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0194342
X-RAY DIFFRACTIONr_bond_other_d0.0020.024084
X-RAY DIFFRACTIONr_angle_refined_deg1.4231.9695886
X-RAY DIFFRACTIONr_angle_other_deg0.96539416
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1175516
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.57423.75192
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.38115742
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4351530
X-RAY DIFFRACTIONr_chiral_restr0.0750.2622
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215100
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02974
X-RAY DIFFRACTIONr_mcbond_it3.8536.4662066
X-RAY DIFFRACTIONr_mcbond_other3.8526.4662067
X-RAY DIFFRACTIONr_mcangle_it6.5929.6812574
Refine LS restraints NCS

Ens-ID: 1 / Number: 16560 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.05 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.801→2.874 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.37 57 -
Rwork0.39 1050 -
all-1107 -
obs--80.98 %

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