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- PDB-7ng7: Src kinase bound to eCF506 trapped in inactive conformation -

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Basic information

Entry
Database: PDB / ID: 7ng7
TitleSrc kinase bound to eCF506 trapped in inactive conformation
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsSIGNALING PROTEIN / Src kinase / inhibitor complex / inactive kinase
Function / homology
Function and homology information


regulation of toll-like receptor 3 signaling pathway / positive regulation of non-membrane spanning protein tyrosine kinase activity / primary ovarian follicle growth / regulation of caveolin-mediated endocytosis / positive regulation of ovarian follicle development / cellular response to prolactin / positive regulation of platelet-derived growth factor receptor-beta signaling pathway / positive regulation of male germ cell proliferation / dendritic filopodium / regulation of cell projection assembly ...regulation of toll-like receptor 3 signaling pathway / positive regulation of non-membrane spanning protein tyrosine kinase activity / primary ovarian follicle growth / regulation of caveolin-mediated endocytosis / positive regulation of ovarian follicle development / cellular response to prolactin / positive regulation of platelet-derived growth factor receptor-beta signaling pathway / positive regulation of male germ cell proliferation / dendritic filopodium / regulation of cell projection assembly / regulation of cell-cell adhesion / response to mineralocorticoid / positive regulation of dephosphorylation / Regulation of commissural axon pathfinding by SLIT and ROBO / ERBB2 signaling pathway / regulation of epithelial cell migration / entry of bacterium into host cell / positive regulation of protein transport / Regulation of gap junction activity / BMP receptor binding / positive regulation of lamellipodium morphogenesis / cellular response to progesterone stimulus / regulation of vascular permeability / Activated NTRK2 signals through FYN / positive regulation of integrin activation / negative regulation of focal adhesion assembly / positive regulation of protein processing / skeletal muscle cell proliferation / : / intestinal epithelial cell development / Netrin mediated repulsion signals / regulation of intracellular estrogen receptor signaling pathway / CD28 co-stimulation / positive regulation of glucose metabolic process / transcytosis / Activated NTRK3 signals through PI3K / connexin binding / cellular response to fluid shear stress / response to acidic pH / focal adhesion assembly / signal complex assembly / positive regulation of small GTPase mediated signal transduction / positive regulation of Ras protein signal transduction / podosome / regulation of bone resorption / positive regulation of podosome assembly / Regulation of RUNX1 Expression and Activity / branching involved in mammary gland duct morphogenesis / adherens junction organization / DCC mediated attractive signaling / myoblast proliferation / EPH-Ephrin signaling / odontogenesis / negative regulation of mitochondrial depolarization / Ephrin signaling / cellular response to peptide hormone stimulus / osteoclast development / Signal regulatory protein family interactions / cellular response to fatty acid / MET activates PTK2 signaling / regulation of early endosome to late endosome transport / Regulation of KIT signaling / Signaling by ALK / postsynaptic specialization, intracellular component / Receptor Mediated Mitophagy / CTLA4 inhibitory signaling / GP1b-IX-V activation signalling / oogenesis / interleukin-6-mediated signaling pathway / leukocyte migration / phospholipase activator activity / DNA biosynthetic process / Fc-gamma receptor signaling pathway involved in phagocytosis / negative regulation of hippo signaling / EPHA-mediated growth cone collapse / p130Cas linkage to MAPK signaling for integrins / positive regulation of Notch signaling pathway / Signaling by EGFR / cellular response to platelet-derived growth factor stimulus / stress fiber assembly / positive regulation of epithelial cell migration / positive regulation of smooth muscle cell migration / progesterone receptor signaling pathway / RUNX2 regulates osteoblast differentiation / regulation of heart rate by cardiac conduction / Recycling pathway of L1 / dendritic growth cone / stimulatory C-type lectin receptor signaling pathway / PECAM1 interactions / uterus development / phospholipase binding / GRB2:SOS provides linkage to MAPK signaling for Integrins / Long-term potentiation / neurotrophin TRK receptor signaling pathway / RHOU GTPase cycle / platelet-derived growth factor receptor signaling pathway / negative regulation of telomere maintenance via telomerase / negative regulation of anoikis / RET signaling / FCGR activation
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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-UCW / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.5 Å
AuthorsLietha, D. / Unciti-Broceta, A.
Funding support Spain, United Kingdom, 2items
OrganizationGrant numberCountry
Spanish Ministry of Science, Innovation, and UniversitiesRTI2018-099318-B-I00 Spain
Wellcome TrustISSF3 United Kingdom
CitationJournal: Cancer Res. / Year: 2021
Title: A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability.
Authors: Temps, C. / Lietha, D. / Webb, E.R. / Li, X.F. / Dawson, J.C. / Muir, M. / Macleod, K.G. / Valero, T. / Munro, A.F. / Contreras-Montoya, R. / Luque-Ortega, J.R. / Fraser, C. / Beetham, H. / ...Authors: Temps, C. / Lietha, D. / Webb, E.R. / Li, X.F. / Dawson, J.C. / Muir, M. / Macleod, K.G. / Valero, T. / Munro, A.F. / Contreras-Montoya, R. / Luque-Ortega, J.R. / Fraser, C. / Beetham, H. / Schoenherr, C. / Lopalco, M. / Arends, M.J. / Frame, M.C. / Qian, B.Z. / Brunton, V.G. / Carragher, N.O. / Unciti-Broceta, A.
History
DepositionFeb 8, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 15, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 29, 2021Group: Data collection / Database references / Category: citation / pdbx_database_proc / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 10, 2021Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3293
Polymers32,7571
Non-polymers5732
Water4,017223
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area220 Å2
ΔGint4 kcal/mol
Surface area13480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.778, 62.594, 51.442
Angle α, β, γ (deg.)90.000, 98.000, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 32756.562 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: eCF506 / Source: (gene. exp.) Homo sapiens (human) / Gene: SRC, SRC1 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P12931, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-UCW / tert-butyl (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)carbamate / ~{tert}-butyl ~{N}-[4-[4-azanyl-1-[2-[4-(dimethylamino)piperidin-1-yl]ethyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxy-phenyl]carbamate


Mass: 510.632 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H38N8O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 223 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.03 Å3/Da / Density % sol: 39.51 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 6% PEG3350, 300mM Ammonium acetate, 0.1M HEPES pH7.5, 10mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.97912 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 4, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97912 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 41802 / % possible obs: 99.4 % / Redundancy: 3.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.043 / Net I/σ(I): 11.7
Reflection shellResolution: 1.5→1.539 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.763 / Num. unique obs: 2933 / CC1/2: 0.626 / Rpim(I) all: 0.493 / % possible all: 99.52

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimlessdata scaling
PHASERphasing
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MXO

4mxo


Resolution: 1.5→41.41 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.945 / SU B: 3.106 / SU ML: 0.058 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.08 / ESU R Free: 0.082 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2133 2192 5.2 %RANDOM
Rwork0.18 ---
obs0.1818 39589 99.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 50.89 Å2 / Biso mean: 17.634 Å2 / Biso min: 8.69 Å2
Baniso -1Baniso -2Baniso -3
1-0.1 Å20 Å2-0.02 Å2
2--0.02 Å20 Å2
3----0.11 Å2
Refinement stepCycle: final / Resolution: 1.5→41.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2213 0 41 223 2477
Biso mean--13.95 26.89 -
Num. residues----274
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0132309
X-RAY DIFFRACTIONr_bond_other_d0.0040.0172196
X-RAY DIFFRACTIONr_angle_refined_deg1.6131.6813130
X-RAY DIFFRACTIONr_angle_other_deg1.4971.6075062
X-RAY DIFFRACTIONr_dihedral_angle_1_deg11.0225272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.94921.87123
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.7415399
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.0771517
X-RAY DIFFRACTIONr_chiral_restr0.0750.2284
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022560
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02529
LS refinement shellResolution: 1.5→1.539 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.301 149 -
Rwork0.27 2933 -
all-3082 -
obs--99.52 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.890.5898-0.49891.8681-1.47453.1935-0.0202-0.169-0.2175-0.0145-0.1321-0.14890.23540.22430.15230.0590.03020.0190.11650.03390.1453-14.482-4.6082.162
20.6851-0.13420.01840.60840.01520.5758-0.0052-0.0138-0.01590.0020.0175-0.02690.00410.0249-0.01220.002-0.00470.01160.0344-0.00210.1137-10.4223.312-21.556
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A263 - 342
2X-RAY DIFFRACTION2A345 - 536

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