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- PDB-6wak: A crystal structure of EGFR(T790M/V948R) in complex with LN3754 -

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Basic information

Entry
Database: PDB / ID: 6wak
TitleA crystal structure of EGFR(T790M/V948R) in complex with LN3754
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Cancer / inhibitor
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-TQA / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsHeppner, D.E. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA201049 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Design of a "Two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites.
Authors: Wittlinger, F. / Heppner, D.E. / To, C. / Gunther, M. / Shin, B.H. / Rana, J.K. / Schmoker, A.M. / Beyett, T.S. / Berger, L.M. / Berger, B.T. / Bauer, N. / Vasta, J.D. / Corona, C.R. / ...Authors: Wittlinger, F. / Heppner, D.E. / To, C. / Gunther, M. / Shin, B.H. / Rana, J.K. / Schmoker, A.M. / Beyett, T.S. / Berger, L.M. / Berger, B.T. / Bauer, N. / Vasta, J.D. / Corona, C.R. / Robers, M.B. / Knapp, S. / Janne, P.A. / Eck, M.J. / Laufer, S.A.
History
DepositionMar 25, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 31, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 1, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Feb 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.3Oct 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

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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
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,09811
Polymers149,9174
Non-polymers2,1807
Water3,783210
1
D: Epidermal growth factor receptor
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,0206
Polymers74,9592
Non-polymers1,0614
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5060 Å2
ΔGint-42 kcal/mol
Surface area26150 Å2
MethodPISA
2
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,0785
Polymers74,9592
Non-polymers1,1193
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4840 Å2
ΔGint-32 kcal/mol
Surface area27110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.472, 103.371, 87.249
Angle α, β, γ (deg.)90.000, 101.240, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 702 through 722 or resid 724...
21(chain B and (resid 702 through 722 or resid 724...
31(chain C and (resid 702 through 722 or resid 724...
41(chain D and (resid 702 through 722 or resid 724...

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
11ALAALAALAALA(chain A and (resid 702 through 722 or resid 724...AB702 - 7228 - 28
12GLYGLYALAALA(chain A and (resid 702 through 722 or resid 724...AB724 - 75030 - 56
13LYSLYSLYSLYS(chain A and (resid 702 through 722 or resid 724...AB754 - 86060 - 166
14VALVALSERSER(chain A and (resid 702 through 722 or resid 724...AB876 - 921182 - 227
15ILEILEALAALA(chain A and (resid 702 through 722 or resid 724...AB923 - 1013229 - 319
21ALAALAALAALA(chain B and (resid 702 through 722 or resid 724...BC702 - 7228 - 28
22GLYGLYALAALA(chain B and (resid 702 through 722 or resid 724...BC724 - 75030 - 56
23LYSLYSLYSLYS(chain B and (resid 702 through 722 or resid 724...BC754 - 86060 - 166
24VALVALSERSER(chain B and (resid 702 through 722 or resid 724...BC876 - 921182 - 227
25ILEILEGLUGLU(chain B and (resid 702 through 722 or resid 724...BC923 - 1005229 - 311
26VALVALALAALA(chain B and (resid 702 through 722 or resid 724...BC1011 - 1013317 - 319
31ALAALAALAALA(chain C and (resid 702 through 722 or resid 724...CD702 - 7228 - 28
32GLYGLYALAALA(chain C and (resid 702 through 722 or resid 724...CD724 - 75030 - 56
33GLNGLNTQATQA(chain C and (resid 702 through 722 or resid 724...CD - K701 - 13017
34ILEILEGLUGLU(chain C and (resid 702 through 722 or resid 724...CD923 - 1005229 - 311
35VALVALALAALA(chain C and (resid 702 through 722 or resid 724...CD1011 - 1013317 - 319
41ALAALAALAALA(chain D and (resid 702 through 722 or resid 724...DA702 - 7228 - 28
42GLYGLYLYSLYS(chain D and (resid 702 through 722 or resid 724...DA724 - 86030 - 166
43VALVALSERSER(chain D and (resid 702 through 722 or resid 724...DA876 - 921182 - 227
44ILEILEGLUGLU(chain D and (resid 702 through 722 or resid 724...DA923 - 1005229 - 311
45VALVALALAALA(chain D and (resid 702 through 722 or resid 724...DA1011 - 1013317 - 319

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Components

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


Mass: 37479.367 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-TQA / N-(3-{5-[2-(acetylamino)pyridin-4-yl]-2-(methylsulfanyl)-1H-imidazol-4-yl}phenyl)-2-[(1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzamide


Mass: 588.679 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C33H28N6O3S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 210 / Source method: isolated from a natural source / Formula: H2O
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: 2.12 Å3/Da / Density % sol: 42.1 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 25% PEG-3350, 0.1 M BisTris

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.4→85.59 Å / Num. obs: 48288 / % possible obs: 97.6 % / Redundancy: 3 % / CC1/2: 0.959 / Rmerge(I) obs: 0.15 / Rpim(I) all: 0.108 / Rrim(I) all: 0.186 / Net I/σ(I): 7.3 / Num. measured all: 145758 / Scaling rejects: 2028
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.4-2.4630.7751068635510.3110.5880.979396.7
10.73-85.593.10.06317985770.9830.0460.07813.197.7

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Aimlessdata scaling
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6P1D

6p1d


Resolution: 2.4→85.58 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 23.79 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2295 2357 4.92 %
Rwork0.2184 45559 -
obs0.219 47916 96.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 104.34 Å2 / Biso mean: 30.9033 Å2 / Biso min: 5.83 Å2
Refinement stepCycle: final / Resolution: 2.4→85.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9732 0 139 210 10081
Biso mean--30.12 30.32 -
Num. residues----1209
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A5528X-RAY DIFFRACTION17.287TORSIONAL
12B5528X-RAY DIFFRACTION17.287TORSIONAL
13C5528X-RAY DIFFRACTION17.287TORSIONAL
14D5528X-RAY DIFFRACTION17.287TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 17

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4-2.450.26931280.25322461258989
2.45-2.50.29751400.26242621276194
2.5-2.560.30711600.25242595275595
2.56-2.620.27461400.25162623276396
2.62-2.690.29931340.24982715284997
2.69-2.770.22231200.25212632275295
2.77-2.860.27491340.25022644277896
2.86-2.960.30361150.25692751286698
2.96-3.080.25151300.24222759288999
3.08-3.220.24181460.2422741288799
3.22-3.390.25221430.23562712285598
3.39-3.60.25431310.22752699283098
3.6-3.880.23281300.20422686281697
3.88-4.270.17841450.1842775292099
4.27-4.890.19481610.16662714287598
4.89-6.160.19761460.19452682282896
6.16-85.580.15981540.19072749290397

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