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- PDB-6z4b: Crystal Structure of EGFR-T790M/V948R in Complex with Osimertinib... -

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Basic information

Entry
Database: PDB / ID: 6z4b
TitleCrystal Structure of EGFR-T790M/V948R in Complex with Osimertinib and EAI045
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR
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 / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB4 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 phosphorylation / positive regulation of glial cell proliferation / 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 / positive regulation of DNA repair / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / ossification / positive regulation of synaptic transmission, glutamatergic / neurogenesis / cellular response to dexamethasone stimulus / basal plasma membrane / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / epithelial cell proliferation / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / clathrin-coated endocytic vesicle membrane / lung development / Constitutive Signaling by EGFRvIII / 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 / Downregulation of ERBB2 signaling / kinase binding / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-9LL / Chem-Q6K / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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: Acs Med.Chem.Lett. / Year: 2020
Title: Complex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands.
Authors: Niggenaber, J. / Heyden, L. / Grabe, T. / Muller, M.P. / Lategahn, J. / Rauh, D.
History
DepositionMay 25, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 11, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 30, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,65816
Polymers75,9282
Non-polymers2,73114
Water45025
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4259
Polymers37,9641
Non-polymers1,4618
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,2337
Polymers37,9641
Non-polymers1,2696
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.200, 79.700, 89.200
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and ((resid 700 through 702 and (name N...
21(chain B and ((resid 700 through 702 and (name N...

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
11ASNASNALAALA(chain A and ((resid 700 through 702 and (name N...AA700 - 70211 - 13
12ASNASNGLNGLN(chain A and ((resid 700 through 702 and (name N...AA700 - 98211 - 293
13ASNASNGLNGLN(chain A and ((resid 700 through 702 and (name N...AA700 - 98211 - 293
14ASNASNGLNGLN(chain A and ((resid 700 through 702 and (name N...AA700 - 98211 - 293
15ASNASNGLNGLN(chain A and ((resid 700 through 702 and (name N...AA700 - 98211 - 293
21ASNASNALAALA(chain B and ((resid 700 through 702 and (name N...BB700 - 70211 - 13
22PROPROASPASP(chain B and ((resid 700 through 702 and (name N...BB699 - 98410 - 295
23PROPROASPASP(chain B and ((resid 700 through 702 and (name N...BB699 - 98410 - 295
24PROPROASPASP(chain B and ((resid 700 through 702 and (name N...BB699 - 98410 - 295
25PROPROASPASP(chain B and ((resid 700 through 702 and (name N...BB699 - 98410 - 295

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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.: 2 / 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-Q6K / ~{N}-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide


Mass: 501.623 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H35N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-9LL / (2R)-2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)-N-(1,3-thiazol-2-yl)acetamide


Mass: 383.396 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H14FN3O3S
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 25 / 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

Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 27.5 % PEG3350, 100 mM MgSO4, 4 % ethylen glycole, 4.7 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: 0.9998 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 5, 2020
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9998 Å / Relative weight: 1
ReflectionResolution: 2.5→44.6 Å / Num. obs: 19371 / % possible obs: 100 % / Redundancy: 6.57 % / CC1/2: 0.998 / Rrim(I) all: 0.109 / Net I/σ(I): 11.15
Reflection shellResolution: 2.5→2.6 Å / Redundancy: 6.49 % / Mean I/σ(I) obs: 1.92 / Num. unique obs: 2099 / CC1/2: 0.695 / Rrim(I) all: 1.085 / % possible all: 99.9

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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: 2.5→44.6 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 26.48 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2513 969 5 %
Rwork0.2207 18393 -
obs0.2222 19362 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 122.52 Å2 / Biso mean: 59.2924 Å2 / Biso min: 31.48 Å2
Refinement stepCycle: final / Resolution: 2.5→44.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4111 0 178 25 4314
Biso mean--66.82 51.14 -
Num. residues----534
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2293X-RAY DIFFRACTION11.304TORSIONAL
12B2293X-RAY DIFFRACTION11.304TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.5-2.630.31451370.305725942731
2.63-2.80.28241340.273125622696
2.8-3.010.28771370.267125842721
3.01-3.320.25781370.245326172754
3.32-3.80.25671380.219426192757
3.8-4.780.23051400.185426522792
4.78-44.60.24061460.210527652911
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)
13.23460.44821.05053.7216-0.13832.793-0.0219-0.3510.2950.1905-0.07040.0061-0.0681-0.0710.06120.35960.05680.00040.5105-0.01010.395839.8475-3.90063.2831
21.8718-0.5716-0.5812.53070.8751.4602-0.0512-0.0260.0499-0.04440.0661-0.11040.09460.06960.00410.361-0.0024-0.00480.39470.05050.381750.3936-6.457-20.6023
31.85480.52540.19766.38161.3890.8550.0329-0.0528-0.1872-0.08-0.00760.05170.1446-0.08990.03950.4275-0.0446-0.03470.52770.04310.430520.6009-10.3436-10.5858
45.36430.36121.03712.12750.28942.4872-0.1569-0.2480.5347-0.10190.08390.2409-0.1823-0.43340.09010.40250.0318-0.02970.4413-0.00910.50378.815210.1617-8.2914
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 701 through 797 )A701 - 797
2X-RAY DIFFRACTION2chain 'A' and (resid 798 through 982 )A798 - 982
3X-RAY DIFFRACTION3chain 'B' and (resid 700 through 853 )B700 - 853
4X-RAY DIFFRACTION4chain 'B' and (resid 854 through 984 )B854 - 984

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