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- PDB-7a6i: Crystal Structure of EGFR-T790M/V948R in Complex with LDC8201 -

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Basic information

Entry
Database: PDB / ID: 7a6i
TitleCrystal Structure of EGFR-T790M/V948R in Complex with LDC8201
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M/V948R / Exon20 / covalent
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-R1W / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsNiggenaber, J. / Mueller, M.P. / Rauh, D.
Funding support Germany, 3items
OrganizationGrant numberCountry
German Federal Ministry for Education and ResearchBMBF 01GS08104 Germany
German Federal Ministry for Education and ResearchBMBF 01ZX1303C Germany
European Regional Development FundEFRE-800400 Germany
CitationJournal: J.Med.Chem. / Year: 2022
Title: Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors.
Authors: Lategahn, J. / Tumbrink, H.L. / Schultz-Fademrecht, C. / Heimsoeth, A. / Werr, L. / Niggenaber, J. / Keul, M. / Parmaksiz, F. / Baumann, M. / Menninger, S. / Zent, E. / Landel, I. / Weisner, ...Authors: Lategahn, J. / Tumbrink, H.L. / Schultz-Fademrecht, C. / Heimsoeth, A. / Werr, L. / Niggenaber, J. / Keul, M. / Parmaksiz, F. / Baumann, M. / Menninger, S. / Zent, E. / Landel, I. / Weisner, J. / Jeyakumar, K. / Heyden, L. / Russ, N. / Muller, F. / Lorenz, C. / Bragelmann, J. / Spille, I. / Grabe, T. / Muller, M.P. / Heuckmann, J.M. / Klebl, B.M. / Nussbaumer, P. / Sos, M.L. / Rauh, D.
History
DepositionAug 25, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 23, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: Database references / Category: citation / citation_author
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 / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 25, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 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
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8366
Polymers37,9641
Non-polymers8725
Water37821
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area690 Å2
ΔGint-48 kcal/mol
Surface area13350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.760, 90.160, 107.720
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number24
Space group name H-MI212121
Components on special symmetry positions
IDModelComponents
11A-1220-

HOH

21A-1221-

HOH

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Components

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


Mass: 37963.910 Da / Num. of mol.: 1 / Mutation: T790M, V948R
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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-R1W / ~{N}-[5-[4-chloranyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-1~{H}-pyrrolo[2,3-b]pyridin-3-yl]-2-methyl-phenyl]propanamide


Mass: 488.024 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H30ClN5O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / 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: 2.2 Å3/Da / Density % sol: 44.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 27.5 % PEG3350, 200 mM MgSO4, 4 % ethylen glycole, 7.5 mg/mL EGFR-T790M/V948R (in 100 mM NaCl, 25 mM Tris-HCl, 10 % glycerol, 1 mM TCEP, pH 8.0) 1 ul reservoir + 1 ul protein solution)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 24, 2018
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→45.08 Å / Num. obs: 13423 / % possible obs: 99.7 % / Redundancy: 12.48 % / CC1/2: 0.999 / Rrim(I) all: 0.102 / Net I/σ(I): 19.07
Reflection shellResolution: 2.4→2.5 Å / Redundancy: 12.4 % / Mean I/σ(I) obs: 2.29 / Num. unique obs: 1513 / CC1/2: 0.774 / Rrim(I) all: 1.161 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6S8A

6s8a


Resolution: 2.4→45.08 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 28.32
RfactorNum. reflection% reflection
Rfree0.2391 672 5.01 %
Rwork0.2022 --
obs0.2041 13417 99.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 126.39 Å2 / Biso mean: 58.5084 Å2 / Biso min: 30.3 Å2
Refinement stepCycle: final / Resolution: 2.4→45.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2199 0 55 21 2275
Biso mean--72.01 56.22 -
Num. residues----282
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 5

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4-2.590.32261330.282625122645100
2.59-2.850.29271320.262525092641100
2.85-3.260.31211340.238725422676100
3.26-4.10.22151340.192825422676100
4.1-45.080.20161390.17272640277999
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)
13.3369-0.5184-0.54182.57750.09833.25680.1309-0.6782-0.16930.1954-0.0536-0.13890.25950.1648-0.03270.4824-0.03530.030.4669-0.00620.390711.6622-15.305317.0395
22.0011.12841.56751.94830.4992.63960.031-0.33890.11710.12470.02090.0808-0.0594-0.11390.00850.4726-0.05290.0820.5509-0.06210.37576.0618-5.704618.4168
33.4311-0.92930.10412.4746-0.48532.28610.14090.2262-0.0337-0.1428-0.14080.06480.2438-0.1678-0.00730.3654-0.00530.05260.3556-0.01070.35650.0578-6.1110.3886
42.8462-0.45010.31562.1755-0.16132.54350.0756-0.17590.55430.2315-0.20370.1453-0.7129-0.4942-0.03360.69030.03430.1430.442-0.08430.67410.48439.387314.0914
52.53490.307-0.76613.81951.02663.97040.15010.31530.66-0.3992-0.1415-0.0431-0.71-0.0669-0.01970.45940.08580.08680.3280.08640.47051.98599.9673-4.6614
64.11180.60450.03671.4092-0.55573.33980.21040.5927-0.3052-0.4669-0.31220.54450.1098-0.69480.11810.46340.1439-0.05280.7229-0.07150.5256-10.5478-2.9668-10.3898
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 703 through 752 )A703 - 752
2X-RAY DIFFRACTION2chain 'A' and (resid 753 through 791 )A753 - 791
3X-RAY DIFFRACTION3chain 'A' and (resid 792 through 853 )A792 - 853
4X-RAY DIFFRACTION4chain 'A' and (resid 854 through 873 )A854 - 873
5X-RAY DIFFRACTION5chain 'A' and (resid 874 through 960 )A874 - 960
6X-RAY DIFFRACTION6chain 'A' and (resid 961 through 984 )A961 - 984

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