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- PDB-7zyq: Crystal Structure of EGFR-T790M/V948R in Complex with Reversible ... -

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Basic information

Entry
Database: PDB / ID: 7zyq
TitleCrystal Structure of EGFR-T790M/V948R in Complex with Reversible Aminopyrimidine 13
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M/V948R / inhibitor
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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / negative regulation of epidermal growth factor receptor signaling pathway / eyelid development in camera-type eye / 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 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / ossification / SHC1 events in ERBB2 signaling / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / positive regulation of DNA replication / epithelial cell proliferation / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / EGFR downregulation / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / cell-cell adhesion / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / cell morphogenesis / positive regulation of fibroblast proliferation / neuron differentiation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / cell junction / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / Cargo recognition for clathrin-mediated endocytosis / PIP3 activates AKT signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / virus receptor activity / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / 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 / positive regulation of ERK1 and ERK2 cascade
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-V58 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsNiggenaber, J. / Mueller, M.P. / Rauh, D.
Funding support Germany, European Union, 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-800400European Union
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines.
Authors: Grabe, T. / Jeyakumar, K. / Niggenaber, J. / Schulz, T. / Koska, S. / Kleinbolting, S. / Beck, M.E. / Muller, M.P. / Rauh, D.
History
DepositionMay 25, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 3, 2023Provider: repository / Type: Initial release
Revision 1.1May 31, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 7, 2024Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,53111
Polymers75,9282
Non-polymers1,6039
Water2,324129
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7906
Polymers37,9641
Non-polymers8265
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7425
Polymers37,9641
Non-polymers7784
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.890, 79.590, 89.570
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 or (resid 701 through 702...
21(chain B and (resid 700 through 761 or (resid 762...

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
11ASNASNASNASN(chain A and (resid 700 or (resid 701 through 702...AA70011
12GLNGLNALAALA(chain A and (resid 700 or (resid 701 through 702...AA701 - 70212 - 13
13ASNASNASPASP(chain A and (resid 700 or (resid 701 through 702...AA700 - 98411 - 295
14ASNASNASPASP(chain A and (resid 700 or (resid 701 through 702...AA700 - 98411 - 295
15ASNASNASPASP(chain A and (resid 700 or (resid 701 through 702...AA700 - 98411 - 295
16ASNASNASPASP(chain A and (resid 700 or (resid 701 through 702...AA700 - 98411 - 295
21ASNASNASPASP(chain B and (resid 700 through 761 or (resid 762...BB700 - 76111 - 72
22GLUGLUALAALA(chain B and (resid 700 through 761 or (resid 762...BB762 - 76373 - 74
23ASNASNASPASP(chain B and (resid 700 through 761 or (resid 762...BB700 - 98411 - 295
24ASNASNASPASP(chain B and (resid 700 through 761 or (resid 762...BB700 - 98411 - 295
25ASNASNASPASP(chain B and (resid 700 through 761 or (resid 762...BB700 - 98411 - 295
26ASNASNASPASP(chain B and (resid 700 through 761 or (resid 762...BB700 - 98411 - 295

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Components

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Protein , 1 types, 2 molecules AB

#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
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

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Non-polymers , 5 types, 138 molecules

#2: Chemical ChemComp-V58 / phenyl 2-[[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxy-phenyl]amino]-4-(1H-indol-3-yl)pyrimidine-5-carboxylate


Mass: 562.661 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H34N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: Na
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 129 / Source method: isolated from a natural source / Formula: H2O

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Details

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, 2 % ethylen glycole, 6.4 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 EIGER2 X 16M / Detector: PIXEL / Date: Feb 17, 2021
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→46.82 Å / Num. obs: 32296 / % possible obs: 99.9 % / Redundancy: 6.73 % / CC1/2: 0.999 / Rrim(I) all: 0.066 / Net I/σ(I): 16.92
Reflection shellResolution: 2.1→2.2 Å / Redundancy: 6.66 % / Mean I/σ(I) obs: 2.75 / Num. unique obs: 4144 / CC1/2: 0.809 / Rrim(I) all: 0.781 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6S89

6s89


Resolution: 2.1→46.82 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 23.27 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.223 1615 5 %
Rwork0.1978 30679 -
obs0.199 32294 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 112.44 Å2 / Biso mean: 50.739 Å2 / Biso min: 26.89 Å2
Refinement stepCycle: final / Resolution: 2.1→46.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4130 0 107 129 4366
Biso mean--47.06 49.22 -
Num. residues----530
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2396X-RAY DIFFRACTION5.292TORSIONAL
12B2396X-RAY DIFFRACTION5.292TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.1-2.160.31841310.265725002631
2.16-2.230.25731340.239525362670
2.23-2.310.21281320.234725062638
2.31-2.40.27561320.222825222654
2.4-2.510.26611330.232825232656
2.51-2.650.32131340.222225352669
2.65-2.810.26011340.222425432677
2.81-3.030.24991330.233225382671
3.03-3.330.21791350.206325702705
3.33-3.820.211360.1825762712
3.82-4.810.17361370.157725952732
4.81-46.820.2161440.194727352879
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)
11.9815-0.0755-0.30871.52130.1692.98580.0065-0.25220.0410.1382-0.009-0.0695-0.0083-0.0040.01830.2659-0.0035-0.01290.29630.01160.343440.843-5.8555-3.7992
23.76990.26650.33713.62650.48162.575-0.04880.1315-0.071-0.25820.0335-0.3245-0.09620.20970.02250.3120.01030.06040.28930.04090.317753.5048-6.1703-22.8076
32.68870.2513-0.40764.2385-0.2951.5231-0.12880.0888-0.4261-0.46290.1865-0.05030.2404-0.1124-0.0230.36-0.0449-0.02630.35150.02890.334120.7351-9.9786-10.1794
45.23861.28190.8582.7458-0.45952.9192-0.3571-0.02020.4489-0.3470.34520.5655-0.1503-0.59480.04160.33280.0245-0.06540.43140.09440.41129.2099.9792-8.5332
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 700 through 853 )A700 - 853
2X-RAY DIFFRACTION2chain 'A' and (resid 854 through 984 )A854 - 984
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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