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- PDB-3u4w: Src in complex with DNA-templated macrocyclic inhibitor MC4b -

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Basic information

Entry
Database: PDB / ID: 3u4w
TitleSrc in complex with DNA-templated macrocyclic inhibitor MC4b
Components
  • Proto-oncogene tyrosine-protein kinase Src
  • macrocyclic inhibitor MC4B
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / Src-like inactive conformation / 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
(2S,5S,8S,13S,16Z)-5-benzyl-2-(cyclohexylmethyl)-3,6,9,15,18-pentaoxo-8-{3-[(pyrazin-2-ylcarbonyl)amino]propyl}-1,4,7,10,14-pentaazacyclooctadec-16-ene-13-carboxylic acid / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.9 Å
AuthorsSeeliger, M.A. / Liu, D.R. / Georghiou, G. / Kleiner, R.E. / Pulkoski-Gross, M.
CitationJournal: Nat.Chem.Biol. / Year: 2012
Title: Highly specific, bisubstrate-competitive Src inhibitors from DNA-templated macrocycles.
Authors: Georghiou, G. / Kleiner, R.E. / Pulkoski-Gross, M. / Liu, D.R. / Seeliger, M.A.
History
DepositionOct 10, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2012Provider: repository / Type: Initial release
Revision 1.1Mar 7, 2012Group: Database references
Revision 1.2Apr 4, 2012Group: Database references
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Sep 23, 2020Group: Derived calculations / Category: struct_conn / struct_site
Item: _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id ..._struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Sep 13, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / pdbx_validate_main_chain_plane / pdbx_validate_rmsd_angle / pdbx_validate_torsion / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_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: macrocyclic inhibitor MC4B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,05110
Polymers32,2942
Non-polymers7578
Water5,855325
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2960 Å2
ΔGint-54 kcal/mol
Surface area12620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)143.610, 143.610, 41.510
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number150
Space group name H-MP321
Components on special symmetry positions
IDModelComponents
11A-917-

HOH

21A-986-

HOH

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Components

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


Mass: 31557.336 Da / Num. of mol.: 1 / Fragment: Src kinase domain (UNP residues 259-533)
Source method: isolated from a genetically manipulated source
Details: as published in Protein Science 14(12):3135-3139 / Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC / Plasmid: pET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Protein/peptide macrocyclic inhibitor MC4B


Type: Peptide-like / Class: Inhibitor / Mass: 736.814 Da / Num. of mol.: 1 / Source method: obtained synthetically
References: (2S,5S,8S,13S,16Z)-5-benzyl-2-(cyclohexylmethyl)-3,6,9,15,18-pentaoxo-8-{3-[(pyrazin-2-ylcarbonyl)amino]propyl}-1,4,7,10,14-pentaazacyclooctadec-16-ene-13-carboxylic acid
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 325 / 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: 3.92 Å3/Da / Density % sol: 68.59 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 3% glycerol, 200 mM ammonium sulfate, pH 8, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 21, 2011
RadiationMonochromator: Rosenbaum-Rock double crystal sagittal focusing
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 1.9→41.457 Å / Num. all: 38862 / Num. obs: 38862 / % possible obs: 100 % / Redundancy: 6 % / Rsym value: 0.098 / Net I/σ(I): 13.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.9-25.80.4211.83274856290.42199.9
2-2.125.90.2812.73113053080.28199.9
2.12-2.275.90.2173.52982850270.217100
2.27-2.4560.1594.72813446920.159100
2.45-2.696.10.12462602242810.124100
2.69-36.10.0878.52413139250.087100
3-3.476.20.06310.92135934640.063100
3.47-4.255.80.05311.71705929270.053100
4.25-6.016.20.04313.11420223070.043100
6.01-41.4576.20.03814.8809213020.03899.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
PHASERphasing
PHENIX1.7.1_743refinement
PDB_EXTRACT3.1data extraction
CBASSdata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2SRC

2src


Resolution: 1.9→39.375 Å / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.9111 / SU ML: 0.4 / σ(F): 1.34 / Phase error: 15.99 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1858 1418 3.65 %
Rwork0.1624 --
obs0.1633 38853 99.95 %
Solvent computationShrinkage radii: 0.72 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 38.452 Å2 / ksol: 0.379 e/Å3
Displacement parametersBiso max: 74.62 Å2 / Biso mean: 18.6498 Å2 / Biso min: 4.9 Å2
Baniso -1Baniso -2Baniso -3
1-1.2138 Å20 Å2-0 Å2
2--1.2138 Å20 Å2
3----2.4276 Å2
Refinement stepCycle: LAST / Resolution: 1.9→39.375 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2266 0 43 325 2634
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072358
X-RAY DIFFRACTIONf_angle_d1.1173190
X-RAY DIFFRACTIONf_chiral_restr0.072334
X-RAY DIFFRACTIONf_plane_restr0.009406
X-RAY DIFFRACTIONf_dihedral_angle_d20.395902
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.9-1.96810.20571420.190137413883
1.9681-2.04680.2231400.173136873827
2.0468-2.140.19331410.169136863827
2.14-2.25280.18441390.162437083847
2.2528-2.39390.18141420.156737373879
2.3939-2.57870.18731360.160537483884
2.5787-2.83820.1941420.162637203862
2.8382-3.24870.20381420.153637673909
3.2487-4.09240.15391430.142337753918
4.0924-39.38320.18481510.178638664017

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