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- PDB-5jeb: Crystal structure of EGFR tyrosine kinase domain with novel inhib... -

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Basic information

Entry
Database: PDB / ID: 5jeb
TitleCrystal structure of EGFR tyrosine kinase domain with novel inhibitor of active state of HER2
ComponentsEpidermal growth factor receptor
KeywordsTransferase/Transferase Inhibitor / Inhibitor / Kinase / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / tongue development / Inhibition of Signaling by Overexpressed EGFR ...response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / tongue development / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / midgut development / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / hydrogen peroxide metabolic process / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / response to cobalamin / Signaling by ERBB4 / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Respiratory syncytial virus (RSV) attachment and entry / 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 / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / cellular response to epidermal growth factor stimulus / EGFR Transactivation by Gastrin / transmembrane receptor protein tyrosine kinase activity / cellular response to cadmium ion / GRB2 events in ERBB2 signaling / positive regulation of DNA repair / neurogenesis / SHC1 events in ERBB2 signaling / regulation of ERK1 and ERK2 cascade / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / positive regulation of epithelial cell proliferation / neuron projection morphogenesis / epithelial cell proliferation / basal plasma membrane / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / cellular response to estradiol stimulus / liver regeneration / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / lung development / Signaling by ERBB2 TMD/JMD mutants / positive regulation of smooth muscle cell proliferation / EGFR downregulation / positive regulation of MAP kinase activity / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / receptor protein-tyrosine kinase / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / kinase binding / peptidyl-tyrosine phosphorylation / Downregulation of ERBB2 signaling / cell-cell adhesion / positive regulation of miRNA transcription / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-6JS / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.298 Å
AuthorsPark, J.H. / Lemmon, M.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01-GM099891 United States
CitationJournal: Nat.Chem.Biol. / Year: 2016
Title: Overcoming resistance to HER2 inhibitors through state-specific kinase binding.
Authors: Novotny, C.J. / Pollari, S. / Park, J.H. / Lemmon, M.A. / Shen, W. / Shokat, K.M.
History
DepositionApr 18, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 7, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 21, 2016Group: Database references
Revision 1.2Nov 2, 2016Group: Database references
Revision 1.3Sep 27, 2017Group: Advisory / Author supporting evidence / Derived calculations
Category: pdbx_audit_support / pdbx_struct_oper_list / pdbx_unobs_or_zero_occ_atoms
Item: _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Sep 27, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)39,1224
Polymers38,5571
Non-polymers5653
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)69.435, 69.435, 191.520
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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


Mass: 38556.578 Da / Num. of mol.: 1 / Fragment: UNP residues 696-1022 / Mutation: V924R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pFastBac / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-6JS / 3-(furan-2-yl)-N-[5-(furan-2-yl)-2-methoxyphenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine


Mass: 373.365 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H15N5O3

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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: 3.46 Å3/Da / Density % sol: 68.33 %
Crystal growTemperature: 294.15 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 1.34M Ammonium sulfate, 1.34% (v/v) PEG 400, and 0.1M sodium acetate/acetic acid

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.0332 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 20, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 3.298→50 Å / Num. obs: 8562 / % possible obs: 99.7 % / Redundancy: 3.4 % / Rsym value: 0.057 / Net I/σ(I): 21.4
Reflection shellResolution: 3.298→3.36 Å / Redundancy: 3.5 % / Mean I/σ(I) obs: 1.26 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1M17

1m17


Resolution: 3.298→34.717 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 31.63
RfactorNum. reflection% reflection
Rfree0.2703 427 4.99 %
Rwork0.2423 --
obs0.2437 8562 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 368.44 Å2 / Biso mean: 149.818 Å2 / Biso min: 66.52 Å2
Refinement stepCycle: final / Resolution: 3.298→34.717 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2308 0 38 0 2346
Biso mean--126.62 --
Num. residues----299
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032403
X-RAY DIFFRACTIONf_angle_d0.6283273
X-RAY DIFFRACTIONf_chiral_restr0.042365
X-RAY DIFFRACTIONf_plane_restr0.004413
X-RAY DIFFRACTIONf_dihedral_angle_d16.437867
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 3 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
3.2978-3.77450.31531560.273926112767
3.7745-4.75350.26661200.255226932813
4.7535-34.71940.26251510.230428312982
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)
10.3850.4380.19850.5260.13630.3453-0.186-0.0875-0.6637-0.31730.24710.07840.33140.09150.07791.31850.4095-0.19420.76230.23171.1221-9.100197.792910.8119
20.22590.0797-0.4510.4695-0.49591.1567-0.0411-0.34510.16110.1156-0.488-0.0156-0.27690.5142-0.05131.09180.43780.131.10460.01170.8531-12.105399.632211.4667
31.8734-0.0256-0.91740.29290.04690.7774-0.19490.3524-0.10530.4255-0.03090.07480.39230.0032-0.07571.15920.4332-0.09620.6096-0.00660.7287-29.0802107.645422.2034
40.16750.17710.01180.18650.01040.02360.3649-0.2409-0.2117-0.2931-0.22920.55210.78220.5444-0.00491.76880.0821-0.5051.23560.39171.369-9.7307105.335836.1056
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 675 through 699 )A675 - 699
2X-RAY DIFFRACTION2chain 'A' and (resid 700 through 752 )A700 - 752
3X-RAY DIFFRACTION3chain 'A' and (resid 753 through 959 )A753 - 959
4X-RAY DIFFRACTION4chain 'A' and (resid 960 through 975 )A960 - 975

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