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- PDB-6s8a: Crystal Structure of EGFR-T790M/C797S in Complex with Covalent Py... -

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Basic information

Entry
Database: PDB / ID: 6s8a
TitleCrystal Structure of EGFR-T790M/C797S in Complex with Covalent Pyrrolopyrimidine 19h
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M/C797S / covalent Pyrrolopyrimide
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / 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 prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / 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 / response to UV-A / epidermal growth factor binding / PLCG1 events in ERBB2 signaling / tongue development / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / regulation of nitric-oxide synthase activity / ERBB2 Activates PTK6 Signaling / morphogenesis of an epithelial fold / intracellular vesicle / Signaling by EGFR / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / : / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of glial cell proliferation / positive regulation of phosphorylation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / positive regulation of DNA repair / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / regulation of ERK1 and ERK2 cascade / basal plasma membrane / neuron projection morphogenesis / positive regulation of superoxide anion generation / epithelial cell proliferation / positive regulation of DNA replication / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / liver regeneration / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / positive regulation of smooth muscle cell proliferation / lung development / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / positive regulation of MAP kinase activity / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / cell-cell adhesion / Downregulation of ERBB2 signaling / ruffle membrane / cellular response to reactive oxygen species
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-L0N / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 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: Chem Sci / Year: 2019
Title: Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S.
Authors: Lategahn, J. / Keul, M. / Klovekorn, P. / Tumbrink, H.L. / Niggenaber, J. / Muller, M.P. / Hodson, L. / Flasshoff, M. / Hardick, J. / Grabe, T. / Engel, J. / Schultz-Fademrecht, C. / ...Authors: Lategahn, J. / Keul, M. / Klovekorn, P. / Tumbrink, H.L. / Niggenaber, J. / Muller, M.P. / Hodson, L. / Flasshoff, M. / Hardick, J. / Grabe, T. / Engel, J. / Schultz-Fademrecht, C. / Baumann, M. / Ketzer, J. / Muhlenberg, T. / Hiller, W. / Gunther, G. / Unger, A. / Muller, H. / Heimsoeth, A. / Golz, C. / Blank-Landeshammer, B. / Kollipara, L. / Zahedi, R.P. / Strohmann, C. / Hengstler, J.G. / van Otterlo, W.A.L. / Bauer, S. / Rauh, D.
History
DepositionJul 9, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 16, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,4233
Polymers37,7161
Non-polymers7082
Water362
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area290 Å2
ΔGint2 kcal/mol
Surface area14550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)142.000, 142.000, 142.000
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23

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Components

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


Mass: 37715.613 Da / Num. of mol.: 1 / Mutation: T790M, C797S, E865A, E866A, K867A
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-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#3: Chemical ChemComp-L0N / ~{N}-[3-[6-[4-(4-methylpiperazin-1-yl)phenyl]-4-(2-methylpropoxy)-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]propanamide


Mass: 512.646 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H36N6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 3.35 Å3/Da / Density % sol: 63.26 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 1.15 K-Na-tartrate, 100 mM Na-MES (pH 6.5), 2 % 1,3-Propanediol, 5.3 mg/ml EGFR T790M/C797 (in 100 mM NaCl, 25mM Tris-HCl, 10 % Glycerol, 1mM TCEP, pH 8.0), 1 ul reservoir + 1 ul protein solution
PH range: 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9791 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 10, 2019
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.6→44.9 Å / Num. obs: 14819 / % possible obs: 100 % / Redundancy: 19.95 % / CC1/2: 1 / Rrim(I) all: 0.079 / Net I/σ(I): 25.86
Reflection shellResolution: 2.6→2.7 Å / Redundancy: 21.13 % / Mean I/σ(I) obs: 2.04 / Num. unique obs: 1572 / CC1/2: 0.738 / Rrim(I) all: 1.802 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5j9z

5j9z


Resolution: 2.6→44.9 Å / SU ML: 0.44 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 26.06
RfactorNum. reflection% reflection
Rfree0.2074 741 5 %
Rwork0.1855 --
obs0.1866 14819 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 171.1 Å2 / Biso mean: 84.1026 Å2 / Biso min: 46.69 Å2
Refinement stepCycle: final / Resolution: 2.6→44.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2425 0 50 2 2477
Biso mean--115.64 81.73 -
Num. residues----313
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042531
X-RAY DIFFRACTIONf_angle_d0.7453439
X-RAY DIFFRACTIONf_chiral_restr0.046387
X-RAY DIFFRACTIONf_plane_restr0.005428
X-RAY DIFFRACTIONf_dihedral_angle_d13.8681537
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.6004-2.80110.4091470.31472806
2.8011-3.08290.27211460.23872774
3.0829-3.52890.25471470.21292792
3.5289-4.44540.17591480.16282813
4.4454-44.90.18491530.17022893
Refinement TLS params.Method: refined / Origin x: 56.5224 Å / Origin y: 7.2401 Å / Origin z: -24.0131 Å
111213212223313233
T0.4037 Å2-0.0438 Å2-0.0225 Å2-0.5304 Å2-0.0142 Å2--0.4057 Å2
L1.4847 °21.2411 °20.6644 °2-3.8701 °21.4972 °2--1.978 °2
S-0.0865 Å °-0.1488 Å °-0.0951 Å °-0.1278 Å °-0.135 Å °0.2727 Å °-0.0249 Å °-0.3314 Å °-0.0083 Å °
Refinement TLS groupSelection details: (chain A and resseq 697:1018)

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