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- PDB-5u8l: Crystal structure of EGFR kinase domain in complex with a sulfony... -

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Basic information

Entry
Database: PDB / ID: 5u8l
TitleCrystal structure of EGFR kinase domain in complex with a sulfonyl fluoride probe XO44
ComponentsEpidermal growth factor receptor
KeywordsTransferase/Transferase Inhibitor / Kinase Covalent probe Covalent inhibitor Complex / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity ...response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / response to UV-A / epidermal growth factor binding / PLCG1 events in ERBB2 signaling / tongue development / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / regulation of nitric-oxide synthase activity / ERBB2 Activates PTK6 Signaling / morphogenesis of an epithelial fold / intracellular vesicle / Signaling by EGFR / response to cobalamin / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB4 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / : / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / positive regulation of DNA repair / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / neurogenesis / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / basal plasma membrane / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / epithelial cell proliferation / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / liver regeneration / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / positive regulation of smooth muscle cell proliferation / lung development / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / positive regulation of MAP kinase activity / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / cell-cell adhesion / cell surface receptor protein tyrosine kinase signaling pathway / Downregulation of ERBB2 signaling / ruffle membrane
Similarity search - Function
: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / 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-O44 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsGajiwala, K.S. / Ferre, R.
CitationJournal: J. Am. Chem. Soc. / Year: 2017
Title: Broad-Spectrum Kinase Profiling in Live Cells with Lysine-Targeted Sulfonyl Fluoride Probes.
Authors: Zhao, Q. / Ouyang, X. / Wan, X. / Gajiwala, K.S. / Kath, J.C. / Jones, L.H. / Burlingame, A.L. / Taunton, J.
History
DepositionDec 14, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 1, 2017Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3074
Polymers37,5801
Non-polymers7273
Water4,738263
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.364, 69.977, 110.403
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Epidermal growth factor receptor / / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 37580.453 Da / Num. of mol.: 1 / Fragment: UNP residues 695-1022
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-O44 / 4-[(4-{4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-6-[(prop-2-yn-1-yl)carbamoyl]pyrimidin-2-yl}piperazin-1-yl)methyl]benzene-1-sulfonyl fluoride


Mass: 538.597 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27FN8O3S
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 263 / 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: 2.07 Å3/Da / Density % sol: 40.71 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: Salt: 0.2 M Ammonium sulfate Buffer: 0.1 M HEPES (pH 7.50) Precipitant: 20.0 %w/v PEG 8000 Precipitant: 5.7 %v/v iso-propanol

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 11, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.41→110.4 Å / Num. obs: 58368 / % possible obs: 99.9 % / Redundancy: 6.5 % / Biso Wilson estimate: 18.2 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.1 / Net I/σ(I): 10.2
Reflection shellResolution: 1.41→1.48 Å / Redundancy: 6.6 % / Rmerge(I) obs: 1.088 / Mean I/σ(I) obs: 2.3 / CC1/2: 0.838 / % possible all: 99.6

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Processing

Software
NameVersionClassification
CNX2005refinement
XDSdata reduction
Aimlessdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→59.11 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 1350640.89 / Data cutoff low absF: 0 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.202 2038 4.8 %RANDOM
Rwork0.189 ---
obs0.19 42092 99.9 %-
Solvent computationBsol: 48.2742 Å2 / ksol: 0.377931 e/Å3
Displacement parametersBiso mean: 22.5 Å2
Baniso -1Baniso -2Baniso -3
1-10.46 Å20 Å20 Å2
2---5.34 Å20 Å2
3----5.12 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.18 Å0.17 Å
Luzzati d res low-5 Å
Luzzati sigma a0.16 Å0.16 Å
Refinement stepCycle: 1 / Resolution: 1.6→59.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2399 0 11 263 2673
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d18.3
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.66
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.211.5
X-RAY DIFFRACTIONc_mcangle_it1.912
X-RAY DIFFRACTIONc_scbond_it2.282
X-RAY DIFFRACTIONc_scangle_it3.412.5
LS refinement shellResolution: 1.6→1.7 Å / Rfactor Rfree error: 0.015 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.252 298 4.3 %
Rwork0.25 6611 -
obs--99.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep-edited.paramprotein-edited.top
X-RAY DIFFRACTION2ACCELRYS_CNX:libraries/toppar/dna-rna_rep.paraACCELRYS_CNX:libraries/toppar/dna-rna.top
X-RAY DIFFRACTION3ACCELRYS_CNX:libraries/toppar/water_rep.paramACCELRYS_CNX:libraries/toppar/water.top
X-RAY DIFFRACTION4ACCELRYS_CNX:libraries/toppar/ion.paramACCELRYS_CNX:libraries/toppar/ion.top

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