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- PDB-6p8q: EGFR in complex with a dihydrodibenzodiazepinone allosteric inhibitor. -

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Basic information

Entry
Database: PDB / ID: 6p8q
TitleEGFR in complex with a dihydrodibenzodiazepinone allosteric inhibitor.
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE Inhibitor complex
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma ...positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / response to cobalamin / 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 / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of bone resorption / embryonic placenta development / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of peptidyl-serine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / basal plasma membrane / Signal transduction by L1 / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / cellular response to estradiol stimulus / lung development / EGFR downregulation / synaptic membrane / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / Constitutive Signaling by EGFRvIII / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / Signaling by ERBB2 ECD mutants
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
ADENOSINE MONOPHOSPHATE / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Chem-O57 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsYun, C.H. / Heppner, 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
DepositionJun 7, 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 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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

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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)153,07126
Polymers149,5694
Non-polymers3,50122
Water18,9521052
1
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,47211
Polymers74,7852
Non-polymers1,6879
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5570 Å2
ΔGint-48 kcal/mol
Surface area27530 Å2
MethodPISA
2
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,59915
Polymers74,7852
Non-polymers1,81413
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5470 Å2
ΔGint-36 kcal/mol
Surface area26920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.151, 72.874, 79.927
Angle α, β, γ (deg.)100.160, 103.160, 95.610
Int Tables number1
Space group name H-MP1

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Components

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Protein , 1 types, 4 molecules ABCD

#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
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 , 6 types, 1074 molecules

#2: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#3: Chemical
ChemComp-O57 / 10-benzyl-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one


Mass: 318.344 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H15FN2O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-AMP / ADENOSINE MONOPHOSPHATE


Mass: 347.221 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H14N5O7P / Comment: AMP*YM
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1052 / 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

CrystalDensity Matthews: 2.11 Å3/Da / Density % sol: 41.73 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: PEG 3350, Bis-Tris

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jul 26, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 87992 / % possible obs: 91 % / Redundancy: 2 % / Rmerge(I) obs: 0.06 / Χ2: 1.049 / Net I/σ(I): 9.7 / Num. measured all: 173254
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.9-1.941.50.28740511.122163
1.94-1.991.70.28149331.058176.1
1.99-2.051.80.25354821.053184.7
2.05-2.111.90.21557831.07190.3
2.11-2.1720.19759151.07192.1
2.17-2.2520.15860301.002193.3
2.25-2.3420.14360491.027193.8
2.34-2.4520.12761021.035194.7
2.45-2.5820.11361561.03195.1
2.58-2.7420.09161551.055195.6
2.74-2.9520.07162021.074196.1
2.95-3.2520.05462551.006196.7
3.25-3.7220.03962551.035197.3
3.72-4.6820.0363241.074198
4.68-5020.02763001.079197.6

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
HKL-2000data scaling
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GS7

2gs7


Resolution: 1.9→21.439 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.97 / Phase error: 20.1
RfactorNum. reflection% reflection
Rfree0.1946 4395 5.01 %
Rwork0.1681 --
obs0.1694 87711 91.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 87.88 Å2 / Biso mean: 25.9068 Å2 / Biso min: 8.27 Å2
Refinement stepCycle: final / Resolution: 1.9→21.439 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9801 0 237 1052 11090
Biso mean--22.72 33.3 -
Num. residues----1221
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.9-1.92160.3093910.25391783187459
1.9216-1.94420.3041120.24432049216168
1.9442-1.96790.24951140.23522283239773
1.9679-1.99280.25061280.23652421254981
1.9928-2.0190.29051400.23212549268983
2.019-2.04660.2371620.22032627278987
2.0466-2.07580.24041290.20542694282389
2.0758-2.10680.23231460.19722822296892
2.1068-2.13970.25091440.19512792293691
2.1397-2.17470.23291480.18822814296293
2.1747-2.21220.22791620.18692854301693
2.2122-2.25240.21921640.18242824298894
2.2524-2.29570.20691500.18382876302694
2.2957-2.34250.19861340.18012849298394
2.3425-2.39330.21621460.18272917306395
2.3933-2.44890.21011520.17942878303094
2.4489-2.51010.21161660.18112915308195
2.5101-2.57780.19961630.17172874303796
2.5778-2.65360.18481550.17392922307795
2.6536-2.7390.1761590.17042892305196
2.739-2.83670.19191780.16832928310696
2.8367-2.950.22781430.16922936307996
2.95-3.08390.19611610.17262927308897
3.0839-3.2460.18491470.16112989313697
3.246-3.44860.17841420.15272964310697
3.4486-3.71360.18681300.14492994312498
3.7136-4.0850.15491500.13323004315498
4.085-4.67070.1311550.12892992314798
4.6707-5.86460.17711740.15753002317699
5.8646-21.44020.17271500.1592945309597

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