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- PDB-7k1h: EGFR L858R/V948R in complex with osimertinib and allosteric inhib... -

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Basic information

Entry
Database: PDB / ID: 7k1h
TitleEGFR L858R/V948R in complex with osimertinib and allosteric inhibitor JBJ-09-063
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / EGFR / kinase / allosteric / 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 / 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 / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / 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 / 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-VNS / Chem-YY3 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.602 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
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)232,76918
Polymers226,4316
Non-polymers6,33812
Water1,820101
1
B: Epidermal growth factor receptor
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,5906
Polymers75,4772
Non-polymers2,1134
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3140 Å2
ΔGint-21 kcal/mol
Surface area26300 Å2
MethodPISA
2
C: Epidermal growth factor receptor
F: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,5906
Polymers75,4772
Non-polymers2,1134
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3110 Å2
ΔGint-19 kcal/mol
Surface area26020 Å2
MethodPISA
3
D: Epidermal growth factor receptor
E: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,5906
Polymers75,4772
Non-polymers2,1134
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3020 Å2
ΔGint-19 kcal/mol
Surface area25590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.848, 88.336, 93.841
Angle α, β, γ (deg.)118.250, 87.050, 106.710
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 701 through 858 or resid 876 through 1007))
21(chain B and resid 701 through 1007)
31chain C
41(chain D and (resid 701 through 858 or resid 876 through 1007))
51(chain E and (resid 701 through 858 or resid 876 through 1007))
61(chain F and resid 701 through 1007)

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 701 through 858 or resid 876 through 1007))A701 - 858
121(chain A and (resid 701 through 858 or resid 876 through 1007))A876 - 1007
211(chain B and resid 701 through 1007)B701 - 1007
311chain CC701 - 1007
411(chain D and (resid 701 through 858 or resid 876 through 1007))D701 - 858
421(chain D and (resid 701 through 858 or resid 876 through 1007))D876 - 1007
511(chain E and (resid 701 through 858 or resid 876 through 1007))E701 - 858
521(chain E and (resid 701 through 858 or resid 876 through 1007))E876 - 1007
611(chain F and resid 701 through 1007)F701 - 1007

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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.: 6 / 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-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.: 6 / Source method: obtained synthetically / Formula: C31H29FN4O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-YY3 / N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide / Osimertinib / AZD 9291


Mass: 499.607 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C28H33N7O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 101 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.05 Å3/Da / Density % sol: 40.13 % / Mosaicity: 0.234 °
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1 M Bis-Tris pH 5.5, 30% (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: 2.6→73.79 Å / Num. obs: 102625 / % possible obs: 93.8 % / Redundancy: 3.8 % / Biso Wilson estimate: 55.72 Å2 / Rpim(I) all: 0.097 / Rrim(I) all: 0.19 / Net I/σ(I): 5.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all% possible all
2.6-2.653.81.5858722660.6171.21183.3
7.06-73.823.711.5962625790.0340.06794.5

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Processing

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

5d41


Resolution: 2.602→46.69 Å / SU ML: 0.44 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 33.74 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2752 3924 3.82 %
Rwork0.231 98701 -
obs0.2327 102625 92.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 142.43 Å2 / Biso mean: 67.9739 Å2 / Biso min: 28.43 Å2
Refinement stepCycle: final / Resolution: 2.602→46.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14082 0 462 101 14645
Biso mean--30 56.58 -
Num. residues----1743
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00914915
X-RAY DIFFRACTIONf_angle_d1.16220211
X-RAY DIFFRACTIONf_chiral_restr0.0642187
X-RAY DIFFRACTIONf_plane_restr0.0072516
X-RAY DIFFRACTIONf_dihedral_angle_d18.2048921
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A8734X-RAY DIFFRACTION15.613TORSIONAL
12B8734X-RAY DIFFRACTION15.613TORSIONAL
13C8734X-RAY DIFFRACTION15.613TORSIONAL
14D8734X-RAY DIFFRACTION15.613TORSIONAL
15E8734X-RAY DIFFRACTION15.613TORSIONAL
16F8734X-RAY DIFFRACTION15.613TORSIONAL
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.6022-2.63390.40311300.3742325487
2.6339-2.66720.41541470.3632361794
2.6672-2.70230.35051400.3534353594
2.7023-2.73930.3641460.3379364694
2.7393-2.77850.41611410.3359355794
2.7785-2.81990.37361380.321348794
2.8199-2.8640.35791460.3268361394
2.864-2.91090.38951420.3159353393
2.9109-2.96110.38221390.3107348593
2.9611-3.0150.42961450.3068362393
3.015-3.07290.31671370.3051338991
3.0729-3.13570.35331360.3235348490
3.1357-3.20380.38651320.3111341890
3.2038-3.27830.35351250.2731307782
3.2783-3.36030.30751430.2545356193
3.3603-3.45110.26981390.2387353495
3.4511-3.55260.2761450.243370396
3.5526-3.66730.28711420.224359595
3.6673-3.79830.30021430.222359495
3.7983-3.95030.25721470.2094363994
3.9503-4.130.22191410.1967354294
4.13-4.34760.25241350.1733351293
4.3476-4.61970.21451360.1848348291
4.6197-4.9760.22491340.1867332688
4.976-5.47610.25281450.1961370296
5.4761-6.26690.24121460.2038368997
6.2669-7.88940.23141470.2001362996
7.8894-46.690.17791370.1726347592
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)
13.5581-2.0472-0.84214.21970.46051.883-0.00130.0083-0.14340.0839-0.04-0.08550.03320.06910.02990.29660.038-0.01910.34910.00030.3143-6.736-17.949-14.672
22.7283-1.68990.09155.33470.84361.5840.10870.19-0.104-0.0674-0.24480.25820.0073-0.18930.15280.31690.0230.03250.3959-0.01750.35430.962-55.288-26.698
32.2835-0.72320.15894.9826-0.36291.73250.10860.243-0.3225-0.3475-0.15330.0027-0.0211-0.09510.03470.29880.06940.07440.513-0.05920.4473-17.782-68.2282.403
42.4069-1.89620.424.7072-0.63372.075-0.0010.1925-0.36580.07390.0550.11990.1857-0.0752-0.05490.2529-0.02780.01950.3877-0.08470.421124.346-36.673-55.038
55.0091-2.1249-0.47783.23890.40132.13110.15680.04110.2471-0.0747-0.13660.0282-0.2331-0.0407-0.03340.3219-0.0020.0170.3025-0.03650.349512.091-2.324-38.6
62.3622-1.0929-0.75354.1940.7442.3894-0.1162-0.06040.18870.072-0.0807-0.1083-0.1434-0.10990.16230.43460.1133-0.05380.4534-0.03250.5194-24.907-30.63213.786
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN B AND RESID 701:1008 )B701 - 1008
2X-RAY DIFFRACTION2( CHAIN A AND RESID 701:1007 )A701 - 1007
3X-RAY DIFFRACTION3( CHAIN C AND RESID 701:1007 )C701 - 1007
4X-RAY DIFFRACTION4( CHAIN D AND RESID 701:1007 )D701 - 1007
5X-RAY DIFFRACTION5( CHAIN E AND RESID 703:1007 )E703 - 1007
6X-RAY DIFFRACTION6( CHAIN F AND RESID 876:1007 )F876 - 1007

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