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- PDB-7k1i: EGFR kinase (L858R/V948R) in complex with allosteric inhibitor JB... -

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Basic information

Entry
Database: PDB / ID: 7k1i
TitleEGFR kinase (L858R/V948R) in complex with allosteric inhibitor JBJ-09-063
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / EGFR / ErbB1 / kinase / inhibitor / TRANSFERASE / 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 / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / 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 / cellular response to epidermal growth factor stimulus / SHC1 events in ERBB2 signaling / 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 / positive regulation of epithelial cell proliferation / epithelial cell proliferation / liver regeneration / basal plasma membrane / 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 / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / 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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Chem-VNS / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.202 Å
AuthorsBeyett, T.S. / Eck, M.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA201049-05 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)1F32CA247198-01 United States
CitationJournal: Nat Commun / Year: 2022
Title: Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors
Authors: Beyett, T.S. / To, C. / Heppner, D.E. / Rana, J.K. / Schmoker, A.M. / Jang, J. / De Clercq, D.J.H. / Gomez, G. / Scott, D.A. / Gray, N.S. / Janne, P.A. / Eck, M.J.
History
DepositionSep 7, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 15, 2021Provider: repository / Type: Initial release
Revision 1.1May 18, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)38,8264
Polymers37,7391
Non-polymers1,0873
Water00
1
A: Epidermal growth factor receptor
hetero molecules

A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,6518
Polymers75,4772
Non-polymers2,1746
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area5470 Å2
ΔGint-47 kcal/mol
Surface area25080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)148.030, 35.800, 54.800
Angle α, β, γ (deg.)90.000, 100.190, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 37738.539 Da / Num. of mol.: 1 / Fragment: kinase domain / Mutation: L858R, V948R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pTriEX / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-VNS / (2R)-2-(5-fluoro-2-hydroxyphenyl)-2-{6-[4-(1-methylpiperidin-4-yl)phenyl]-1-oxo-1,3-dihydro-2H-isoindol-2-yl}-N-(1,3-thiazol-2-yl)acetamide


Mass: 556.650 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H29FN4O3S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 1.89 Å3/Da / Density % sol: 35.04 % / Mosaicity: 0 °
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1 M Bis-Tris pH 5.5, 28% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 5, 2018
RadiationMonochromator: Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 3.2→53.94 Å / Num. obs: 4805 / % possible obs: 98.8 % / Redundancy: 6.5 % / Biso Wilson estimate: 114.45 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.144 / Rpim(I) all: 0.062 / Rrim(I) all: 0.158 / Net I/σ(I): 7.2 / Num. measured all: 31390 / Scaling rejects: 27
Reflection shell

Diffraction-ID: 1 / Redundancy: 5.8 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
3.2-3.290.92220493510.7210.4031.011.396.3
14.32-53.940.077381660.9920.0340.08514.998.1

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5D41

5d41


Resolution: 3.202→53.936 Å / SU ML: 0.39 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 29.51 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3106 259 5.4 %
Rwork0.2633 4539 -
obs0.2656 4798 98.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 365.42 Å2 / Biso mean: 153.8804 Å2 / Biso min: 30 Å2
Refinement stepCycle: final / Resolution: 3.202→53.936 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2323 0 72 0 2395
Biso mean--128.26 --
Num. residues----288
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062485
X-RAY DIFFRACTIONf_angle_d0.8183373
X-RAY DIFFRACTIONf_chiral_restr0.049370
X-RAY DIFFRACTIONf_plane_restr0.006417
X-RAY DIFFRACTIONf_dihedral_angle_d16.571497
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
3.202-4.03380.40951200.3318224398
4.0338-53.9360.27351390.2414229699
Refinement TLS params.Method: refined / Origin x: 17.3615 Å / Origin y: -14.9412 Å / Origin z: 8.3435 Å
111213212223313233
T1.0387 Å2-0.1849 Å2-0.032 Å2-1.1639 Å2-0.3407 Å2--0.9985 Å2
L6.774 °20.1803 °22.1206 °2-3.2383 °2-0.6202 °2--5.6437 °2
S-0.1911 Å °0.1094 Å °-0.1248 Å °0.8561 Å °0.5309 Å °-0.6323 Å °-1.1769 Å °2.3652 Å °-0.1959 Å °
Refinement TLS groupSelection details: (chain 'A' and resid 700 through 1007)

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