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- PDB-6v5p: EGFR(T790M/V948R) in complex with LN2725 -

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Basic information

Entry
Database: PDB / ID: 6v5p
TitleEGFR(T790M/V948R) in complex with LN2725
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE inhibitor / egfr / inhibitor / TRANSFERASE-TRANSFERASE inhibitor complex
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 / epidermal growth factor binding / response to UV-A / regulation of peptidyl-tyrosine phosphorylation ...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 / epidermal growth factor binding / response to UV-A / regulation of peptidyl-tyrosine phosphorylation / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / PTK6 promotes HIF1A stabilization / Signaling by EGFR / intracellular vesicle / negative regulation of epidermal growth factor receptor signaling pathway / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / protein insertion into membrane / 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 / MAP kinase kinase kinase activity / GAB1 signalosome / protein tyrosine kinase activator activity / ossification / positive regulation of G1/S transition of mitotic cell cycle / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / positive regulation of epithelial cell proliferation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / positive regulation of fibroblast proliferation / cellular response to amino acid stimulus / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / basal plasma membrane / positive regulation of DNA repair / positive regulation of DNA replication / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of protein localization to plasma membrane / negative regulation of protein catabolic process / clathrin-coated endocytic vesicle membrane / cell-cell adhesion / NOTCH3 Activation and Transmission of Signal to the Nucleus / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / positive regulation of protein phosphorylation / cell junction / epidermal growth factor receptor signaling pathway / ruffle membrane / kinase binding / Downregulation of ERBB2 signaling / Constitutive Signaling by Aberrant PI3K in Cancer / HCMV Early Events / positive regulation of canonical Wnt signaling pathway / actin filament binding / neuron differentiation / transmembrane signaling receptor activity / PIP3 activates AKT signaling / positive regulation of cell growth / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / nuclear membrane / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / RAF/MAP kinase cascade / protein tyrosine kinase activity / double-stranded DNA binding / early endosome membrane / protein phosphatase binding / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / basolateral plasma membrane / positive regulation of MAPK cascade / learning or memory / positive regulation of ERK1 and ERK2 cascade / signaling receptor complex / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / endosome / endosome membrane / positive regulation of cell migration / cadherin binding / membrane raft
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 / 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-QP4 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsHeppner, D.E. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA201049 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors.
Authors: Heppner, D.E. / Gunther, M. / Wittlinger, F. / Laufer, S.A. / Eck, M.J.
History
DepositionDec 4, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 16, 2022Group: Author supporting evidence / Database references / Category: database_2 / pdbx_audit_support
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 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)151,73011
Polymers149,9174
Non-polymers1,8127
Water6,738374
1
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8836
Polymers74,9592
Non-polymers9244
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3380 Å2
ΔGint-44 kcal/mol
Surface area26580 Å2
MethodPISA
2
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8475
Polymers74,9592
Non-polymers8883
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3360 Å2
ΔGint-29 kcal/mol
Surface area26360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.360, 101.610, 87.170
Angle α, β, γ (deg.)90.000, 102.310, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
11(chain A and (resid 701 through 792 or resid 794...
21(chain B and (resid 701 through 792 or resid 794 through 1008 or resid 1101))
31(chain C and (resid 701 through 792 or resid 794 through 1008 or resid 1101))
41(chain D and (resid 701 through 792 or resid 794...

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
11GLNGLNLEULEU(chain A and (resid 701 through 792 or resid 794...AA701 - 7927 - 98
12PROPROLEULEU(chain A and (resid 701 through 792 or resid 794...AA794 - 862100 - 168
13VALVALASPASP(chain A and (resid 701 through 792 or resid 794...AA876 - 1008182 - 314
14QP4QP4QP4QP4(chain A and (resid 701 through 792 or resid 794...AE1101
21GLNGLNLEULEU(chain B and (resid 701 through 792 or resid 794 through 1008 or resid 1101))BB701 - 7927 - 98
22PROPROASPASP(chain B and (resid 701 through 792 or resid 794 through 1008 or resid 1101))BB794 - 1008100 - 314
23QP4QP4QP4QP4(chain B and (resid 701 through 792 or resid 794 through 1008 or resid 1101))BG1101
31GLNGLNLEULEU(chain C and (resid 701 through 792 or resid 794 through 1008 or resid 1101))CC701 - 7927 - 98
32PROPROASPASP(chain C and (resid 701 through 792 or resid 794 through 1008 or resid 1101))CC794 - 1008100 - 314
33QP4QP4QP4QP4(chain C and (resid 701 through 792 or resid 794 through 1008 or resid 1101))CI1101
41GLNGLNLEULEU(chain D and (resid 701 through 792 or resid 794...DD701 - 7927 - 98
42PROPROLEULEU(chain D and (resid 701 through 792 or resid 794...DD794 - 862100 - 168
43VALVALASPASP(chain D and (resid 701 through 792 or resid 794...DD876 - 1008182 - 314
44QP4QP4QP4QP4(chain D and (resid 701 through 792 or resid 794...DJ1101

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Components

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


Mass: 37479.367 Da / Num. of mol.: 4 / Mutation: T790M,V948R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pEX / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-QP4 / 4-[4-(4-fluorophenyl)-2-(3-methoxypropyl)-1H-imidazol-5-yl]-2-phenyl-3H-pyrrolo[2,3-b]pyridine


Mass: 426.485 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H23FN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 374 / 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: 2.03 Å3/Da / Density % sol: 39.43 % / Mosaicity: 0 °
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1 M Bis-Tris, 25% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9791 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.3→40.86 Å / Num. obs: 52870 / % possible obs: 99.2 % / Redundancy: 5.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.036 / Rrim(I) all: 0.084 / Net I/σ(I): 13.9 / Num. measured all: 275491
Reflection shell

Diffraction-ID: 1 / Redundancy: 5.1 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.3-2.360.6521965738920.8060.3210.7282.499
10.29-40.860.02830946110.9990.0140.03139.897.3

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5d41

5d41


Resolution: 2.3→40.86 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 20.11 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1937 2565 4.85 %
Rwork0.1791 50270 -
obs0.1798 52835 99.14 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 110.05 Å2 / Biso mean: 45.3968 Å2 / Biso min: 21.56 Å2
Refinement stepCycle: final / Resolution: 2.3→40.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9789 0 131 374 10294
Biso mean--40.2 45.97 -
Num. residues----1216
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A5578X-RAY DIFFRACTION13.814TORSIONAL
12B5578X-RAY DIFFRACTION13.814TORSIONAL
13C5578X-RAY DIFFRACTION13.814TORSIONAL
14D5578X-RAY DIFFRACTION13.814TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 18

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3-2.340.22481380.21972800293899
2.34-2.390.28221180.2222751286999
2.39-2.440.27061360.22252804294099
2.44-2.50.25781630.21392747291099
2.5-2.560.24361400.204928132953100
2.56-2.630.20841440.19812786293099
2.63-2.710.21981410.1952768290999
2.71-2.80.21071360.19552839297599
2.8-2.90.1851250.191127832908100
2.9-3.010.20121570.187227952952100
3.01-3.150.23691420.18327972939100
3.15-3.320.18531380.18122783292199
3.32-3.520.20371550.18242768292398
3.52-3.80.19081340.17652779291399
3.8-4.180.16111620.161828212983100
4.18-4.780.16841360.15042812294899
4.78-6.020.16781500.17572803295399
6.02-40.860.18961500.17042821297198

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