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- PDB-7jxi: EGFR kinase (T790M/V948R) in complex with PF-06747775 -

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Basic information

Entry
Database: PDB / ID: 7jxi
TitleEGFR kinase (T790M/V948R) in complex with PF-06747775
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / EGFR / ErbB1 / kinase / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE Inhibitor complex
Function / homology
Function and homology information


multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A ...multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / intracellular vesicle / eyelid development in camera-type eye / negative regulation of epidermal growth factor receptor signaling pathway / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / Signaling by ERBB2 / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / EGFR downregulation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / positive regulation of epithelial cell proliferation / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Downregulation of ERBB2 signaling / cell-cell adhesion / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / positive regulation of protein phosphorylation / epidermal growth factor receptor signaling pathway / neuron differentiation / cell morphogenesis / positive regulation of fibroblast proliferation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / Cargo recognition for clathrin-mediated endocytosis / cell junction / transmembrane signaling receptor activity / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / virus receptor activity / ATPase binding / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / double-stranded DNA binding / protein tyrosine kinase activity / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / endosome 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 / 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-8BS / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 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
DepositionAug 27, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 8, 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 ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.3Oct 30, 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
D: Epidermal growth factor receptor
A: Epidermal growth factor receptor
C: Epidermal growth factor receptor
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,5688
Polymers150,8984
Non-polymers1,6704
Water00
1
C: Epidermal growth factor receptor
hetero molecules

D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,2844
Polymers75,4492
Non-polymers8352
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_556x,y,z+11
Buried area3010 Å2
ΔGint-19 kcal/mol
Surface area26280 Å2
MethodPISA
2
A: Epidermal growth factor receptor
hetero molecules

B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,2844
Polymers75,4492
Non-polymers8352
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_556x,y,z+11
Buried area2980 Å2
ΔGint-19 kcal/mol
Surface area25950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.630, 100.778, 87.155
Angle α, β, γ (deg.)90.000, 101.170, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 702 through 748 or resid 757...
21(chain B and (resid 702 through 857 or resid 876...
31(chain C and (resid 702 through 748 or resid 757...
41(chain D and (resid 702 through 748 or resid 757...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ALAALAARGARG(chain A and (resid 702 through 748 or resid 757...AB702 - 74811 - 57
12LYSLYSGLYGLY(chain A and (resid 702 through 748 or resid 757...AB757 - 85766 - 166
13VALVALLEULEU(chain A and (resid 702 through 748 or resid 757...AB876 - 907185 - 216
14THRTHRASPASP(chain A and (resid 702 through 748 or resid 757...AB909 - 984218 - 293
15PROPROGLUGLU(chain A and (resid 702 through 748 or resid 757...AB990 - 1004299 - 313
168BS8BS8BS8BS(chain A and (resid 702 through 748 or resid 757...AF1101
21ALAALAGLYGLY(chain B and (resid 702 through 857 or resid 876...BD702 - 85711 - 166
22VALVALLEULEU(chain B and (resid 702 through 857 or resid 876...BD876 - 907185 - 216
23THRTHRASPASP(chain B and (resid 702 through 857 or resid 876...BD909 - 984218 - 293
24PROPRO8BS8BS(chain B and (resid 702 through 857 or resid 876...BD - H990 - 1101299
31ALAALAARGARG(chain C and (resid 702 through 748 or resid 757...CC702 - 74811 - 57
32LYSLYSLEULEU(chain C and (resid 702 through 748 or resid 757...CC757 - 90766 - 216
33THRTHRASPASP(chain C and (resid 702 through 748 or resid 757...CC909 - 984218 - 293
34PROPROGLUGLU(chain C and (resid 702 through 748 or resid 757...CC990 - 1004299 - 313
358BS8BS8BS8BS(chain C and (resid 702 through 748 or resid 757...CG1101
41ALAALAARGARG(chain D and (resid 702 through 748 or resid 757...DA702 - 74811 - 57
42LYSLYSGLYGLY(chain D and (resid 702 through 748 or resid 757...DA757 - 85766 - 166
43VALVALLEULEU(chain D and (resid 702 through 748 or resid 757...DA876 - 907185 - 216
44THRTHRASPASP(chain D and (resid 702 through 748 or resid 757...DA909 - 984218 - 293
45PROPROGLUGLU(chain D and (resid 702 through 748 or resid 757...DA990 - 1004299 - 313
468BS8BS8BS8BS(chain D and (resid 702 through 748 or resid 757...DE1101

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Components

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


Mass: 37724.598 Da / Num. of mol.: 4 / Fragment: kinase domain / Mutation: T790M, 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-8BS / N-[(3R,4R)-4-fluoro-1-{6-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-9-methyl-9H-purin-2-yl}pyrrolidin-3-yl]propanamide


Mass: 417.441 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H24FN9O2 / Feature type: SUBJECT OF INVESTIGATION
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: 2.02 Å3/Da / Density % sol: 39.01 % / Description: Plate
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-C / Wavelength: 0.9778 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 10, 2019
RadiationMonochromator: Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9778 Å / Relative weight: 1
ReflectionResolution: 3→100.78 Å / Num. obs: 23783 / % possible obs: 98.6 % / Redundancy: 6.5 % / Biso Wilson estimate: 50.76 Å2 / Rpim(I) all: 0.102 / Rrim(I) all: 0.263 / Net I/σ(I): 5.5 / Num. measured all: 154096
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all% possible all
3-3.055.50.9635711660.581.39596.4
8.14-100.836.520.2810812430.0330.08899

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
xia2data scaling
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5D41

5d41


Resolution: 3→85.5 Å / SU ML: 0.49 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 33.65 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3121 1175 4.97 %
Rwork0.2764 22471 -
obs0.2782 23646 98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 121.64 Å2 / Biso mean: 59.5321 Å2 / Biso min: 20.48 Å2
Refinement stepCycle: final / Resolution: 3→85.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9176 0 120 0 9296
Biso mean--49.31 --
Num. residues----1136
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A5456X-RAY DIFFRACTION11.183TORSIONAL
12B5456X-RAY DIFFRACTION11.183TORSIONAL
13C5456X-RAY DIFFRACTION11.183TORSIONAL
14D5456X-RAY DIFFRACTION11.183TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3-3.140.39261390.35492670280994
3.14-3.30.36751380.30972843298199
3.3-3.510.34251450.31362836298199
3.51-3.780.30771360.29322762289897
3.78-4.160.33211470.27342841298899
4.16-4.760.28241650.26772832299799
4.76-60.28631470.26232810295798
6-85.50.29531580.23682877303598
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)
13.2621-0.28750.87442.8933-0.72163.0789-0.0137-0.03780.37920.07720.02920.1153-0.2468-0.00610.03880.2661-0.02530.01410.2434-0.01620.30227.9979-21.03012.773
23.3451-0.7302-0.58282.3639-0.42226.17310.1716-0.0684-0.0182-0.06030.03720.09840.25830.0568-0.22970.34780.0516-0.03760.26970.00240.363125.2613-28.966547.9057
32.2896-0.31120.26921.63390.51735.5014-0.03470.6156-0.0342-0.26760.0865-0.03240.1430.7922-0.08010.30250.0467-0.03820.65060.02570.3664-11.3066-28.626149.0547
44.7959-0.01571.951.49160.05394.5030.0575-0.09330.267-0.06070.08640.2766-0.1913-0.073-0.15940.22430.00720.05890.3601-0.03440.395441.5723-17.51080.6417
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain 'D' and resid 702 through 1101)D702 - 1101
2X-RAY DIFFRACTION2(chain 'A' and resid 700 through 1101)A700 - 1101
3X-RAY DIFFRACTION3(chain 'C' and resid 700 through 1101)C700 - 1101
4X-RAY DIFFRACTION4(chain 'B' and resid 702 through 1101)B702 - 1101

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