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- PDB-6p1l: Crystal structure of EGFR in complex with EAI045 -

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Basic information

Entry
Database: PDB / ID: 6p1l
TitleCrystal structure of EGFR in complex with EAI045
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / egfr / allosteric inhibitor / TRANSFERASE / 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 / 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-9LL / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsHeppner, D.E. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors.
Authors: De Clercq, D.J.H. / Heppner, D.E. / To, C. / Jang, J. / Park, E. / Yun, C.H. / Mushajiang, M. / Shin, B.H. / Gero, T.W. / Scott, D.A. / Janne, P.A. / Eck, M.J. / Gray, N.S.
History
DepositionMay 20, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_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)152,84115
Polymers149,5694
Non-polymers3,27211
Water21612
1
A: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,6128
Polymers74,7852
Non-polymers1,8286
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4960 Å2
ΔGint-41 kcal/mol
Surface area25490 Å2
MethodPISA
2
B: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,2297
Polymers74,7852
Non-polymers1,4445
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5280 Å2
ΔGint-43 kcal/mol
Surface area26410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.600, 103.150, 87.100
Angle α, β, γ (deg.)90.000, 101.180, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 702 through 748 or resid 756 through 1005))
21(chain B and (resid 702 through 748 or resid 756 through 858 or resid 876 through 1005))
31(chain C and resid 702 through 1005)
41(chain D and (resid 702 through 748 or resid 756 through 1005))

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
11ALAALAARGARG(chain A and (resid 702 through 748 or resid 756 through 1005))AA702 - 7487 - 53
12ASNASNGLUGLU(chain A and (resid 702 through 748 or resid 756 through 1005))AA756 - 100561 - 310
21ALAALAARGARG(chain B and (resid 702 through 748 or resid 756 through 858 or resid 876 through 1005))BB702 - 7487 - 53
22ASNASNLEULEU(chain B and (resid 702 through 748 or resid 756 through 858 or resid 876 through 1005))BB756 - 85861 - 163
23VALVALGLUGLU(chain B and (resid 702 through 748 or resid 756 through 858 or resid 876 through 1005))BB876 - 1005181 - 310
31ALAALAGLUGLU(chain C and resid 702 through 1005)CC702 - 10057 - 310
41ALAALAARGARG(chain D and (resid 702 through 748 or resid 756 through 1005))DD702 - 7487 - 53
42ASNASNGLUGLU(chain D and (resid 702 through 748 or resid 756 through 1005))DD756 - 100561 - 310

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Components

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


Mass: 37392.285 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 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: Mg
#3: Chemical
ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: 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.: 3 / Source method: obtained synthetically / Formula: C19H14FN3O3S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: H2O

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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: 2.33 Å3/Da / Density % sol: 42.5 % / Mosaicity: 0 °
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1 M Bis-Tris ,26% PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.8→58.61 Å / Num. obs: 30003 / % possible obs: 96.5 % / Redundancy: 3 % / CC1/2: 0.991 / Rmerge(I) obs: 0.116 / Rpim(I) all: 0.076 / Rrim(I) all: 0.139 / Net I/σ(I): 8.4 / Num. measured all: 91347 / Scaling rejects: 32
Reflection shellResolution: 2.8→2.87 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.673 / Num. measured all: 6038 / Num. unique obs: 2141 / CC1/2: 0.624 / Rpim(I) all: 0.459 / Rrim(I) all: 0.819 / Net I/σ(I) obs: 1.9 / % possible all: 93.5

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
Aimless0.7.4data scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5d41

5d41


Resolution: 2.8→58.609 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 26.32 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2366 1489 4.97 %
Rwork0.201 28497 -
obs0.2027 29986 96.33 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 131.7 Å2 / Biso mean: 51.5565 Å2 / Biso min: 22.37 Å2
Refinement stepCycle: final / Resolution: 2.8→58.609 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9338 0 209 12 9559
Biso mean--47.96 42.03 -
Num. residues----1156
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A5572X-RAY DIFFRACTION17.703TORSIONAL
12B5572X-RAY DIFFRACTION17.703TORSIONAL
13C5572X-RAY DIFFRACTION17.703TORSIONAL
14D5572X-RAY DIFFRACTION17.703TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.8001-2.89050.3681280.30492484261294
2.8905-2.99380.32441510.29622602275397
2.9938-3.11370.36721260.29192531265795
3.1137-3.25540.30081360.2572534267095
3.2554-3.4270.28761360.22852648278498
3.427-3.64170.28881310.20762650278198
3.6417-3.92280.22831410.19372575271697
3.9228-4.31750.19791170.162608272596
4.3175-4.94190.16731420.16042628277098
4.9419-6.22520.19781450.18512582272796
6.2252-58.62150.19931360.17672655279196

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