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- PDB-2rgp: Structure of EGFR in complex with hydrazone, a potent dual inhibitor -

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Basic information

Entry
Database: PDB / ID: 2rgp
TitleStructure of EGFR in complex with hydrazone, a potent dual inhibitor
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Kinase domain / Alternative splicing / Anti-oncogene / ATP-binding / Cell cycle / Disease mutation / Glycoprotein / Membrane / Nucleotide-binding / Phosphoprotein / Polymorphism / Receptor / Secreted / Transmembrane / Tyrosine-protein kinase / Ubl conjugation
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 / tongue development / response to UV-A / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / response to cobalamin / intracellular vesicle / 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 / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of bone resorption / Signaling by ERBB4 / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / positive regulation of phosphorylation / MAP kinase kinase kinase activity / hair follicle development / peptidyl-tyrosine autophosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / embryonic placenta development / positive regulation of peptidyl-serine phosphorylation / salivary gland morphogenesis / positive regulation of vasoconstriction / placental growth factor receptor activity / positive regulation of glial cell proliferation / hepatocyte growth factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / stem cell factor receptor activity / platelet-derived growth factor beta-receptor activity / brain-derived neurotrophic factor receptor activity / platelet-derived growth factor alpha-receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / insulin-like growth factor receptor activity / macrophage colony-stimulating factor receptor activity / Signaling by ERBB2 / GRB2 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GPI-linked ephrin receptor activity / vascular endothelial growth factor receptor activity / GRB2 events in ERBB2 signaling / fibroblast growth factor receptor activity / SHC1 events in ERBB2 signaling / insulin receptor activity / positive regulation of synaptic transmission, glutamatergic / cellular response to dexamethasone stimulus / ossification / liver regeneration / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / positive regulation of epithelial cell proliferation / positive regulation of superoxide anion generation / epithelial cell proliferation / positive regulation of DNA replication / neuron projection morphogenesis / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / astrocyte activation / cellular response to amino acid stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / peptidyl-tyrosine phosphorylation / Constitutive Signaling by EGFRvIII
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-HYZ / PHOSPHATE ION / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsAbad, M.C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: 4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors.
Authors: Xu, G. / Abad, M.C. / Connolly, P.J. / Neeper, M.P. / Struble, G.T. / Springer, B.A. / Emanuel, S.L. / Pandey, N. / Gruninger, R.H. / Adams, M. / Moreno-Mazza, S. / Fuentes-Pesquera, A.R. / Middleton, S.A.
History
DepositionOct 4, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Aug 30, 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7074
Polymers36,0711
Non-polymers6363
Water1,53185
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.850, 68.030, 103.860
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 / Receptor tyrosine-protein kinase ErbB-1


Mass: 36070.809 Da / Num. of mol.: 1 / Fragment: Residues 702-1016
Source method: isolated from a genetically manipulated source
Details: Expressed open reading frame of construct is MHHHHHHVDLVPRGSHMA-(EGFR1 S671-G998
Source: (gene. exp.) Homo sapiens (human) / Strain: human strains undefined / Gene: EGFR, ERBB1 / Plasmid: modified pDEST8 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): sf9
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-HYZ / N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-5-[(piperidin-1-ylamino)methyl]pyrimidine-4,6-diamine


Mass: 446.523 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27FN8
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 85 / 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: 2.25 Å3/Da / Density % sol: 45.22 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 9
Details: 2M Na/K3PO4, 0.1M Caps pH 9.0 and 0.2M Li2SO4, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Feb 22, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.89→50 Å / Num. obs: 26482 / % possible obs: 98.9 % / Redundancy: 3.9 % / Biso Wilson estimate: 33 Å2 / Rmerge(I) obs: 0.046 / Χ2: 1.571 / Net I/σ(I): 15.8
Reflection shellResolution: 2.04→2.13 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.208 / Mean I/σ(I) obs: 7.28 / Num. unique all: 2508 / Χ2: 1.161 / % possible all: 99.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3data extraction
HKL-2000data collection
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1XKK

1xkk


Resolution: 2→50 Å / FOM work R set: 0.793 / Isotropic thermal model: anisotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.268 2248 9.9 %random
Rwork0.228 ---
obs-22479 99.3 %-
Displacement parametersBiso mean: 44.528 Å2
Baniso -1Baniso -2Baniso -3
1--13.327 Å20 Å20 Å2
2--5.606 Å20 Å2
3---7.721 Å2
Refinement stepCycle: LAST / Resolution: 2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2289 0 43 85 2417
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it1.5591.5
X-RAY DIFFRACTIONc_scbond_it2.1122
X-RAY DIFFRACTIONc_mcangle_it2.5992
X-RAY DIFFRACTIONc_scangle_it3.2552.5
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1MSI_CNX_TOPPAR:protein_rep.param
X-RAY DIFFRACTION2inh.par
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:water_rep.param
X-RAY DIFFRACTION4MSI_CNX_TOPPAR:ion.param

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