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- PDB-6wa2: Crystal structure of EGFR(T790M/V948R) in complex with LN3753 -

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Basic information

Entry
Database: PDB / ID: 6wa2
TitleCrystal structure of EGFR(T790M/V948R) in complex with LN3753
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Drug discovery / Cancer
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / positive regulation of prolactin secretion / 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 / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / positive regulation of prolactin secretion / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / tongue development / response to UV-A / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / response to cobalamin / 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 / hepatocyte growth factor receptor activity / platelet-derived growth factor beta-receptor activity / placental growth factor receptor activity / brain-derived neurotrophic factor receptor activity / boss receptor activity / platelet-derived growth factor alpha-receptor activity / epidermal growth factor receptor activity / macrophage colony-stimulating factor receptor activity / protein tyrosine kinase activator activity / protein tyrosine kinase collagen receptor activity / stem cell factor receptor activity / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of bone resorption / Signaling by ERBB4 / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / insulin-like growth factor receptor activity / transmembrane-ephrin receptor activity / positive regulation of phosphorylation / GPI-linked ephrin receptor activity / positive regulation of peptidyl-serine phosphorylation / vascular endothelial growth factor receptor activity / peptidyl-tyrosine autophosphorylation / 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 / fibroblast growth factor receptor activity / embryonic placenta development / insulin receptor activity / salivary gland morphogenesis / positive regulation of vasoconstriction / neuron projection morphogenesis / Signaling by ERBB2 / positive regulation of glial cell proliferation / 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 / cellular response to dexamethasone stimulus / GRB2 events in ERBB2 signaling / positive regulation of synaptic transmission, glutamatergic / 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 / positive regulation of epithelial cell proliferation / EGFR downregulation / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / positive regulation of smooth muscle cell proliferation / positive regulation of protein localization to plasma membrane / liver regeneration / astrocyte activation / cellular response to amino acid stimulus / cellular response to estradiol stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / lung development / synaptic membrane / peptidyl-tyrosine phosphorylation / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII
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-TOV / 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 24, 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)151,93411
Polymers149,9174
Non-polymers2,0167
Water4,234235
1
D: Epidermal growth factor receptor
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,9495
Polymers74,9592
Non-polymers9903
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3280 Å2
ΔGint-33 kcal/mol
Surface area26930 Å2
MethodPISA
2
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,9856
Polymers74,9592
Non-polymers1,0264
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3560 Å2
ΔGint-42 kcal/mol
Surface area26640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.360, 102.470, 87.680
Angle α, β, γ (deg.)90.000, 102.540, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 701 through 748 or resid 751...
21(chain B and (resid 701 through 748 or resid 751...
31(chain C and (resid 701 through 863 or resid 877...
41(chain D and (resid 701 through 748 or resid 751...

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
11GLNGLNARGARG(chain A and (resid 701 through 748 or resid 751...AB701 - 7487 - 54
12THRTHRGLYGLY(chain A and (resid 701 through 748 or resid 751...AB751 - 86357 - 169
13PROPROSERSER(chain A and (resid 701 through 748 or resid 751...AB877 - 921183 - 227
14ILEILEASPASP(chain A and (resid 701 through 748 or resid 751...AB923 - 994229 - 300
15ASNASNASPASP(chain A and (resid 701 through 748 or resid 751...AB996 - 1014302 - 320
21GLNGLNARGARG(chain B and (resid 701 through 748 or resid 751...BC701 - 7487 - 54
22THRTHRGLYGLY(chain B and (resid 701 through 748 or resid 751...BC751 - 86357 - 169
23PROPROSERSER(chain B and (resid 701 through 748 or resid 751...BC877 - 921183 - 227
24ILEILEGLYGLY(chain B and (resid 701 through 748 or resid 751...BC923 - 983229 - 289
25ARGARGASPASP(chain B and (resid 701 through 748 or resid 751...BC986 - 994292 - 300
26ASNASNASPASP(chain B and (resid 701 through 748 or resid 751...BC996 - 1014302 - 320
31GLNGLNGLYGLY(chain C and (resid 701 through 863 or resid 877...CD701 - 8637 - 169
32PROPROSERSER(chain C and (resid 701 through 863 or resid 877...CD877 - 921183 - 227
33ILEILEGLYGLY(chain C and (resid 701 through 863 or resid 877...CD923 - 983229 - 289
34ARGARGASPASP(chain C and (resid 701 through 863 or resid 877...CD986 - 994292 - 300
35ASNASNASPASP(chain C and (resid 701 through 863 or resid 877...CD996 - 1014302 - 320
41GLNGLNARGARG(chain D and (resid 701 through 748 or resid 751...DA701 - 7487 - 54
42THRTHRGLYGLY(chain D and (resid 701 through 748 or resid 751...DA751 - 86357 - 169
43PROPROSERSER(chain D and (resid 701 through 748 or resid 751...DA877 - 921183 - 227
44ILEILEGLYGLY(chain D and (resid 701 through 748 or resid 751...DA923 - 983229 - 289
45ARGARGASPASP(chain D and (resid 701 through 748 or resid 751...DA986 - 994292 - 300
46ASNASNASPASP(chain D and (resid 701 through 748 or resid 751...DA996 - 1014302 - 320

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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-TOV / N-(3-{5-[2-(acetylamino)pyridin-4-yl]-2-(methylsulfanyl)-1H-imidazol-4-yl}phenyl)-2-fluoro-5-hydroxybenzamide


Mass: 477.511 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H20FN5O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 2.07 Å3/Da / Density % sol: 40.69 %
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 PILATUS 6M-F / 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→69.66 Å / Num. obs: 46133 / % possible obs: 95.7 % / Redundancy: 4 % / CC1/2: 0.992 / Rmerge(I) obs: 0.078 / Rpim(I) all: 0.048 / Rrim(I) all: 0.092 / Net I/σ(I): 15.9 / Num. measured all: 186031 / Scaling rejects: 1788
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
2.4-2.463.70.4581167431570.8640.270.5352.888.3
10.73-69.664.30.019239456210.010.0214598.4

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6P1D

6p1d


Resolution: 2.4→69.66 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 32.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2579 2270 4.92 %
Rwork0.2205 43831 -
obs0.2224 46101 95.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 121.12 Å2 / Biso mean: 47.1971 Å2 / Biso min: 14.5 Å2
Refinement stepCycle: final / Resolution: 2.4→69.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9878 0 139 235 10252
Biso mean--41.01 42.34 -
Num. residues----1230
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A5752X-RAY DIFFRACTION16.965TORSIONAL
12B5752X-RAY DIFFRACTION16.965TORSIONAL
13C5752X-RAY DIFFRACTION16.965TORSIONAL
14D5752X-RAY DIFFRACTION16.965TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 16

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4-2.450.38941300.31292506263687
2.45-2.510.35321480.29082672282094
2.51-2.570.35351450.28992764290998
2.57-2.640.33081360.27882810294697
2.64-2.720.35911490.29442761291097
2.72-2.810.32791450.29492722286797
2.81-2.910.38611200.30162799291997
2.91-3.020.37631320.29592754288696
3.02-3.160.35371270.29212714284195
3.16-3.330.33191410.26342648278992
3.33-3.540.311350.23012777291297
3.54-3.810.22731410.19422798293997
3.81-4.190.23561470.17022767291497
4.19-4.80.19391580.16172703286194
4.8-6.050.1681600.17472816297698
6.05-69.660.17091560.17572820297696

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