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- PDB-4lrm: EGFR D770_N771insNPG in complex with PD168393 -

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Basic information

Entry
Database: PDB / ID: 4lrm
TitleEGFR D770_N771insNPG in complex with PD168393
ComponentsEpidermal growth factor receptor
Keywordstransferase/transferase inhibitor / EGFR / Kinase / PD168393 / 34-jab / transferase-transferase inhibitor complex
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma ...positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / eyelid development in camera-type eye / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of bone resorption / embryonic placenta development / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of peptidyl-serine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / basal plasma membrane / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / Signal transduction by L1 / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / cellular response to estradiol stimulus / lung development / EGFR downregulation / synaptic membrane / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / Constitutive Signaling by EGFRvIII / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / Signaling by ERBB2 ECD mutants
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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-YUN / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.526 Å
AuthorsYun, C.H. / Eck, M.J.
CitationJournal: Sci Transl Med / Year: 2013
Title: Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer.
Authors: Yasuda, H. / Park, E. / Yun, C.H. / Sng, N.J. / Lucena-Araujo, A.R. / Yeo, W.L. / Huberman, M.S. / Cohen, D.W. / Nakayama, S. / Ishioka, K. / Yamaguchi, N. / Hanna, M. / Oxnard, G.R. / ...Authors: Yasuda, H. / Park, E. / Yun, C.H. / Sng, N.J. / Lucena-Araujo, A.R. / Yeo, W.L. / Huberman, M.S. / Cohen, D.W. / Nakayama, S. / Ishioka, K. / Yamaguchi, N. / Hanna, M. / Oxnard, G.R. / Lathan, C.S. / Moran, T. / Sequist, L.V. / Chaft, J.E. / Riely, G.J. / Arcila, M.E. / Soo, R.A. / Meyerson, M. / Eck, M.J. / Kobayashi, S.S. / Costa, D.B.
History
DepositionJul 20, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 15, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 20, 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_conn / 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_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
E: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)191,36010
Polymers189,5045
Non-polymers1,8565
Water28816
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2722
Polymers37,9011
Non-polymers3711
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2722
Polymers37,9011
Non-polymers3711
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2722
Polymers37,9011
Non-polymers3711
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2722
Polymers37,9011
Non-polymers3711
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2722
Polymers37,9011
Non-polymers3711
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)114.923, 425.845, 95.100
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 37900.715 Da / Num. of mol.: 5
Fragment: Epidermal Growth Factor Receptor (unp residues 694-1022)
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-YUN / N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}propanamide


Mass: 371.231 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C17H15BrN4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 3.07 Å3/Da / Density % sol: 59.93 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M Tris, 2% PEG400, 5mM tris(2-carboxyethyl)-phosphine (TCEP), pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 16, 2008
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 3.5→50 Å / Num. all: 28970 / Num. obs: 24856 / % possible obs: 85.8 % / Observed criterion σ(I): -1.1 / Redundancy: 2.3 % / Rmerge(I) obs: 0.151 / Net I/σ(I): 5.6
Reflection shellResolution: 3.5→3.77 Å / Redundancy: 2 % / Rmerge(I) obs: 0.389 / Mean I/σ(I) obs: 1.7 / % possible all: 76.1

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
PHENIX(phenix.refine: 1.8_1069)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2JIU

2jiu


Resolution: 3.526→49.181 Å / SU ML: 0.52 / σ(F): 1.36 / Phase error: 28.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2638 1262 5.09 %RANDOM
Rwork0.2249 ---
obs0.2269 24812 84.5 %-
all-29363 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.526→49.181 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11565 0 115 16 11696
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00611962
X-RAY DIFFRACTIONf_angle_d0.98516218
X-RAY DIFFRACTIONf_dihedral_angle_d18.7394473
X-RAY DIFFRACTIONf_chiral_restr0.0691809
X-RAY DIFFRACTIONf_plane_restr0.0092033
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.5262-3.66740.40291230.32821925X-RAY DIFFRACTION64
3.6674-3.83420.34931220.29222446X-RAY DIFFRACTION80
3.8342-4.03630.29591290.26592594X-RAY DIFFRACTION85
4.0363-4.2890.28741430.23162689X-RAY DIFFRACTION88
4.289-4.620.24841580.20752709X-RAY DIFFRACTION89
4.62-5.08450.25421550.19652732X-RAY DIFFRACTION89
5.0845-5.81920.25691630.22392788X-RAY DIFFRACTION90
5.8192-7.32770.25661290.2272830X-RAY DIFFRACTION89
7.3277-49.18570.21511400.19542837X-RAY DIFFRACTION86
Refinement TLS params.Method: refined / Origin x: 31.7361 Å / Origin y: 268.974 Å / Origin z: 24.4121 Å
111213212223313233
T0.4138 Å2-0.0132 Å2-0.0066 Å2-0.4197 Å20.0017 Å2--0.3268 Å2
L0.0266 °20.0985 °2-0.0104 °2-3.0247 °20.3797 °2--0.0325 °2
S-0.0012 Å °-0.0089 Å °-0.0254 Å °0.3503 Å °-0.0183 Å °-0.0049 Å °0.0955 Å °-0.006 Å °0.0154 Å °
Refinement TLS groupSelection details: all

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