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- PDB-6p1d: Crystal structure of EGFR with mutant-selective dihydrodibenzodia... -

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Basic information

Entry
Database: PDB / ID: 6p1d
TitleCrystal structure of EGFR with mutant-selective dihydrodibenzodiazepinone allosteric inhibitor
ComponentsEpidermal growth factor receptor
KeywordsTransferase/Transferase Inhibitor / EGFR / Cancer / Inhibitor / SIGNALING PROTEIN / Transferase-Transferase Inhibitor complex
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Chem-NQ1 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 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 19, 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.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
D: Epidermal growth factor receptor
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,64615
Polymers149,5694
Non-polymers3,07711
Water6,179343
1
B: Epidermal growth factor receptor
hetero molecules

D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,4828
Polymers74,7852
Non-polymers1,6986
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_556x,y,z+11
Buried area5060 Å2
ΔGint-44 kcal/mol
Surface area25380 Å2
MethodPISA
2
A: Epidermal growth factor receptor
hetero molecules

C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,1647
Polymers74,7852
Non-polymers1,3795
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_556x,y,z+11
Buried area5690 Å2
ΔGint-44 kcal/mol
Surface area26640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.946, 101.812, 86.510
Angle α, β, γ (deg.)90.000, 101.040, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 702 through 830 or resid 832...
21(chain B and (resid 702 through 830 or resid 832...
31(chain C and (resid 702 through 830 or resid 832...
41(chain D and (resid 702 through 830 or resid 832...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 702 through 830 or resid 832...A702 - 830
121(chain A and (resid 702 through 830 or resid 832...A832 - 861
131(chain A and (resid 702 through 830 or resid 832...A876 - 921
141(chain A and (resid 702 through 830 or resid 832...A963 - 9
151(chain A and (resid 702 through 830 or resid 832...A971 - 109
161(chain A and (resid 702 through 830 or resid 832...A971 - 1006
171(chain A and (resid 702 through 830 or resid 832...A2003
211(chain B and (resid 702 through 830 or resid 832...B702 - 830
221(chain B and (resid 702 through 830 or resid 832...B832 - 861
231(chain B and (resid 702 through 830 or resid 832...B702 - 1013
241(chain B and (resid 702 through 830 or resid 832...B923 - 944
251(chain B and (resid 702 through 830 or resid 832...B971 - 109
261(chain B and (resid 702 through 830 or resid 832...B971 - 1006
271(chain B and (resid 702 through 830 or resid 832...B2004
311(chain C and (resid 702 through 830 or resid 832...C702 - 830
321(chain C and (resid 702 through 830 or resid 832...C832 - 861
331(chain C and (resid 702 through 830 or resid 832...C876 - 921
341(chain C and (resid 702 through 830 or resid 832...C923 - 944
351(chain C and (resid 702 through 830 or resid 832...C946 - 961
361(chain C and (resid 702 through 830 or resid 832...C963 - 969
371(chain C and (resid 702 through 830 or resid 832...C971 - 1006
381(chain C and (resid 702 through 830 or resid 832...C2002
411(chain D and (resid 702 through 830 or resid 832...D702 - 830
421(chain D and (resid 702 through 830 or resid 832...D832 - 861
431(chain D and (resid 702 through 830 or resid 832...D701 - 1008
441(chain D and (resid 702 through 830 or resid 832...D923 - 944
451(chain D and (resid 702 through 830 or resid 832...D971 - 109
461(chain D and (resid 702 through 830 or resid 832...D971 - 1006
471(chain D and (resid 702 through 830 or resid 832...D2001

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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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pTriEX / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-NQ1 / 10-benzyl-8-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one


Mass: 318.344 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: C20H15FN2O / Feature type: SUBJECT OF INVESTIGATION
#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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 343 / 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: 2.07 Å3/Da / Density % sol: 40.47 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1 M Bis-Tris, 29% PEG 3350, 5.0 mM TCEP

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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: 2.4→65.17 Å / Num. obs: 47635 / % possible obs: 99.5 % / Redundancy: 3.5 % / CC1/2: 0.993 / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.062 / Rrim(I) all: 0.118 / Net I/σ(I): 7.8 / Num. measured all: 167295 / Scaling rejects: 81
Reflection shellResolution: 2.4→2.46 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.358 / Num. measured all: 11646 / Num. unique obs: 3483 / CC1/2: 0.88 / Rpim(I) all: 0.229 / Rrim(I) all: 0.426 / Net I/σ(I) obs: 2.7 / % possible all: 99.2

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
Aimless0.6.3data scaling
PDB_EXTRACT3.25data extraction
PHASERphasing
Cootmodel building
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5d41

5d41


Resolution: 2.4→65.17 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 23.05
RfactorNum. reflection% reflection
Rfree0.2134 2336 4.91 %
Rwork0.1945 --
obs0.1954 47595 99.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 127.29 Å2 / Biso mean: 35.536 Å2 / Biso min: 14.35 Å2
Refinement stepCycle: final / Resolution: 2.4→65.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9635 0 200 343 10178
Biso mean--30.95 34.79 -
Num. residues----1196
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A4151X-RAY DIFFRACTION14.508TORSIONAL
12B4151X-RAY DIFFRACTION14.508TORSIONAL
13C4151X-RAY DIFFRACTION14.508TORSIONAL
14D4151X-RAY DIFFRACTION14.508TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 17

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4-2.44840.31081560.25292525268196
2.4484-2.50160.29381240.25652649277399
2.5016-2.55980.30851290.24542678280799
2.5598-2.62380.29271350.232926542789100
2.6238-2.69480.22391270.22526632790100
2.6948-2.77410.22581410.21926942835100
2.7741-2.86360.26671630.217626112774100
2.8636-2.9660.23571460.20826892835100
2.966-3.08470.23991250.2126842809100
3.0847-3.22510.24061220.209426702792100
3.2251-3.39510.21391340.19952675280999
3.3951-3.60780.22231380.19472656279499
3.6078-3.88630.19321420.17862616275899
3.8863-4.27740.16621260.163327032829100
4.2774-4.89610.15921550.159326672822100
4.8961-6.16790.19491260.187427122838100
6.1679-65.23210.19091470.17422713286099

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