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- PDB-7u98: EGFR(T790M/V948R) in complex with a macrocyclic inhibitor -

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Basic information

Entry
Database: PDB / ID: 7u98
TitleEGFR(T790M/V948R) in complex with a macrocyclic inhibitor
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / EGFR / kinase / macrocycle / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity ...response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / hydrogen peroxide metabolic process / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / protein tyrosine kinase activator activity / response to cobalamin / Signaling by ERBB4 / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of vasoconstriction / positive regulation of glial cell proliferation / Signaling by ERBB2 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / positive regulation of DNA repair / regulation of ERK1 and ERK2 cascade / SHC1 events in ERBB2 signaling / ossification / cellular response to dexamethasone stimulus / neurogenesis / positive regulation of synaptic transmission, glutamatergic / positive regulation of epithelial cell proliferation / neuron projection morphogenesis / basal plasma membrane / epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / lung development / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of smooth muscle cell proliferation / positive regulation of MAP kinase activity / Constitutive Signaling by EGFRvIII / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / kinase binding / Downregulation of ERBB2 signaling / positive regulation of miRNA transcription / cell-cell adhesion / peptidyl-tyrosine phosphorylation / ruffle 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-M1O / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.42 Å
AuthorsBeyett, T.S. / Eck, M.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5F32CA247198-02 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA116020-15 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Macrocyclization of Quinazoline-Based EGFR Inhibitors Leads to Exclusive Mutant Selectivity for EGFR L858R and Del19.
Authors: Amrhein, J.A. / Beyett, T.S. / Feng, W.W. / Kramer, A. / Weckesser, J. / Schaeffner, I.K. / Rana, J.K. / Janne, P.A. / Eck, M.J. / Knapp, S. / Hanke, T.
History
DepositionMar 10, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 23, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 30, 2022Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Dec 21, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 25, 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
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,6988
Polymers150,8984
Non-polymers1,7994
Water00
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1742
Polymers37,7251
Non-polymers4501
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1742
Polymers37,7251
Non-polymers4501
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1742
Polymers37,7251
Non-polymers4501
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1742
Polymers37,7251
Non-polymers4501
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.353, 100.923, 88.309
Angle α, β, γ (deg.)90.000, 102.170, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 702 through 859 or resid 877...
21(chain B and (resid 702 through 748 or resid 755...
31(chain C and (resid 702 through 859 or resid 877...
41(chain D and (resid 702 through 859 or resid 877...

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 859 or resid 877...AA702 - 85911 - 168
12PROPROLEULEU(chain A and (resid 702 through 859 or resid 877...AA877 - 907186 - 216
13THRTHRGLUGLU(chain A and (resid 702 through 859 or resid 877...AA909 - 1005218 - 314
14M1OM1OM1OM1O(chain A and (resid 702 through 859 or resid 877...AE1101
21ALAALAARGARG(chain B and (resid 702 through 748 or resid 755...BB702 - 74811 - 57
22ALAALAALAALA(chain B and (resid 702 through 748 or resid 755...BB755 - 85964 - 168
23PROPROLEULEU(chain B and (resid 702 through 748 or resid 755...BB877 - 907186 - 216
24THRTHRM1OM1O(chain B and (resid 702 through 748 or resid 755...BB - F909 - 1101218
31ALAALAALAALA(chain C and (resid 702 through 859 or resid 877...CC702 - 85911 - 168
32PROPROLEULEU(chain C and (resid 702 through 859 or resid 877...CC877 - 907186 - 216
33THRTHRGLUGLU(chain C and (resid 702 through 859 or resid 877...CC909 - 1005218 - 314
34M1OM1OM1OM1O(chain C and (resid 702 through 859 or resid 877...CG1101
41ALAALAALAALA(chain D and (resid 702 through 859 or resid 877...DD702 - 85911 - 168
42PROPROLEULEU(chain D and (resid 702 through 859 or resid 877...DD877 - 907186 - 216
43THRTHRGLUGLU(chain D and (resid 702 through 859 or resid 877...DD909 - 1005218 - 314
44M1OM1OM1OM1O(chain D and (resid 702 through 859 or resid 877...DH1101

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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, residues 695-1022 / 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-M1O / 19-chloro-18-fluoro-22-methoxy-8,9,11,12,14,15-hexahydro-21H-4,6-ethenopyrimido[5,4-m][1,4,7,10,15]benzotetraoxazacycloheptadecine


Mass: 449.860 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H21ClFN3O5 / 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

CrystalMosaicity: 0.444 °
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-C / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 23, 2021
RadiationMonochromator: Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 3.41→86.32 Å / Num. obs: 16531 / % possible obs: 98.4 % / Redundancy: 3.4 % / Biso Wilson estimate: 82.79 Å2 / Rpim(I) all: 0.109 / Rrim(I) all: 0.204 / Net I/σ(I): 4.5 / Num. measured all: 55699
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.2 %

Resolution (Å)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all% possible all
3.41-3.470.824237480.3610.67690.1
9.26-86.3517.327748630.0430.0898.2

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Processing

Software
NameVersionClassification
xia2data scaling
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
xia2data reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DUK

6duk


Resolution: 3.42→86.32 Å / SU ML: 0.45 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 25.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2441 804 4.89 %
Rwork0.2147 15637 -
obs0.2162 16441 98.23 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 167.26 Å2 / Biso mean: 79.6886 Å2 / Biso min: 36.07 Å2
Refinement stepCycle: final / Resolution: 3.42→86.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9303 0 124 0 9427
Biso mean--73.35 --
Num. residues----1151
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A4208X-RAY DIFFRACTION13.798TORSIONAL
12B4208X-RAY DIFFRACTION13.798TORSIONAL
13C4208X-RAY DIFFRACTION13.798TORSIONAL
14D4208X-RAY DIFFRACTION13.798TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.42-3.630.31941250.27962556268197
3.63-3.910.2941250.25932605273099
3.91-4.30.24731540.19612598275299
4.3-4.930.22191270.18492580270797
4.93-6.210.25221350.21012643277899
6.21-86.320.20691380.20722655279398
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)
12.460.2339-0.97021.6402-0.24253.68940.05640.01-0.2347-0.0503-0.02520.18170.135-0.1120.00740.35820.0162-0.05230.46380.07080.4842-1.496917.159741.2872
21.4340.46350.53582.3014-0.6425.63670.1687-0.17980.25670.0996-0.04520.0154-0.2171-0.227-0.10490.3373-0.03690.06050.48240.01690.5137-2.445726.540980.4959
32.8793-0.15992.31442.5355-1.47556.6146-0.0111-0.2595-0.02410.35550.18330.2103-0.6743-0.2901-0.13470.4994-0.04830.10940.51880.0620.5232-37.161725.720880.6405
42.42070.2177-1.75242.6960.52919.43530.04730.0178-0.0230.03840.21430.0510.33090.1171-0.27110.3314-0.0219-0.05760.573-0.00250.5514-38.12814.914341.289
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain 'A' and resid 701 through 1007)A701 - 1007
2X-RAY DIFFRACTION2(chain 'B' and resid 701 through 1101)B701 - 1101
3X-RAY DIFFRACTION3(chain 'C' and resid 702 through 1007)C702 - 1007
4X-RAY DIFFRACTION4(chain 'D' and resid 701 through 1007)D701 - 1007

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