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- PDB-4jrv: Crystal structure of EGFR kinase domain in complex with compound 4c -

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Basic information

Entry
Database: PDB / ID: 4jrv
TitleCrystal structure of EGFR kinase domain in complex with compound 4c
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Transferase / tyrosine kinase domain / ATP-binding domain / autophosphorylation / 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 / negative regulation of epidermal growth factor receptor signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / Signaling by ERBB4 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein insertion into membrane / eyelid development in camera-type eye / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / activation of phospholipase C activity / positive regulation of cyclin-dependent protein serine/threonine kinase activity / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / regulation of peptidyl-tyrosine phosphorylation / peptidyl-tyrosine autophosphorylation / positive regulation of glial cell proliferation / positive regulation of phosphorylation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / positive regulation of DNA repair / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / cellular response to dexamethasone stimulus / SHC1 events in ERBB2 signaling / 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 / liver regeneration / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / clathrin-coated endocytic vesicle membrane / positive regulation of smooth muscle cell proliferation / lung development / Signaling by ERBB2 TMD/JMD mutants / 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 / negative regulation of protein catabolic process / cell-cell adhesion / receptor protein-tyrosine kinase / ruffle membrane / Downregulation of ERBB2 signaling / cellular response to reactive oxygen species
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-KJV / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsPeng, Y.H. / Wu, J.S.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Protein Kinase Inhibitor Design by Targeting the Asp-Phe-Gly (DFG) Motif: The Role of the DFG Motif in the Design of Epidermal Growth Factor Receptor Inhibitors
Authors: Peng, Y.H. / Shiao, H.Y. / Tu, C.H. / Liu, P.M. / Hsu, J.T. / Amancha, P.K. / Wu, J.S. / Coumar, M.S. / Chen, C.H. / Wang, S.Y. / Lin, W.H. / Sun, H.Y. / Chao, Y.S. / Lyu, P.C. / Hsieh, H.P. / Wu, S.Y.
History
DepositionMar 22, 2013Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 19, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 8, 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_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_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

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9372
Polymers37,4011
Non-polymers5361
Water37821
1
A: Epidermal growth factor receptor
hetero molecules

A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8744
Polymers74,8032
Non-polymers1,0712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_555-x,y,-z1
Buried area2170 Å2
ΔGint-8 kcal/mol
Surface area30130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.391, 146.391, 146.391
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23

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Components

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


Mass: 37401.250 Da / Num. of mol.: 1 / Fragment: EGFR kinase domain, UNP residues 696-1021
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR / Plasmid: pBacPAK-MT-EGFP / Cell line (production host): Hi5 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-KJV / 4-(dimethylamino)-N-[3-(4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl]butanamide


Mass: 535.636 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H33N5O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 21 / 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: 3.49 Å3/Da / Density % sol: 64.81 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 1.0M Ammonium citrate tribase, 0.1M Bis-Tris propane, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL12B2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Feb 11, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. obs: 13039 / % possible obs: 98.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 30.79 % / Rmerge(I) obs: 0.076 / Net I/σ(I): 14.28
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.477 / Mean I/σ(I) obs: 2.53 / Num. unique all: 1248 / % possible all: 98.7

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREP9.2phasing
REFMAC5.6.0117refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1M17

1m17


Resolution: 2.8→29.88 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.908 / SU B: 23.135 / SU ML: 0.215 / Cross valid method: THROUGHOUT / ESU R: 0.561 / ESU R Free: 0.291 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22679 627 4.9 %RANDOM
Rwork0.19255 ---
obs0.19422 12196 98.39 %-
all-13039 --
Solvent computationIon probe radii: 0.9 Å / Shrinkage radii: 0.9 Å / VDW probe radii: 1 Å / Solvent model: MASK
Displacement parametersBiso mean: 82.137 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.8→29.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2392 0 40 21 2453
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.022487
X-RAY DIFFRACTIONr_bond_other_d0.0010.021712
X-RAY DIFFRACTIONr_angle_refined_deg0.9431.9963366
X-RAY DIFFRACTIONr_angle_other_deg0.8383.0054190
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3145297
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.62424.369103
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.55115450
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.4191513
X-RAY DIFFRACTIONr_chiral_restr0.0520.2373
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212681
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02483
LS refinement shellResolution: 2.799→2.871 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.297 45 -
Rwork0.27 856 -
obs--98.79 %
Refinement TLS params.Method: refined / Origin x: -23.848 Å / Origin y: -58.992 Å / Origin z: -10.053 Å
111213212223313233
T0.1132 Å20.0609 Å20.075 Å2-0.087 Å2-0.029 Å2--0.1555 Å2
L2.1153 °2-0.6918 °2-1.0005 °2-1.179 °20.3778 °2--1.9662 °2
S0.2669 Å °0.0636 Å °0.3452 Å °-0.0766 Å °-0.0627 Å °-0.1156 Å °-0.4006 Å °-0.2156 Å °-0.2042 Å °

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