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- PDB-6v5n: EGFR(T790M/V948R) in complex with LN2084 -

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Basic information

Entry
Database: PDB / ID: 6v5n
TitleEGFR(T790M/V948R) in complex with LN2084
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE inhibitor / egfr / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / 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 protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / 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 / epidermal growth factor binding / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / hydrogen peroxide metabolic process / ERBB2-EGFR signaling pathway / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / protein tyrosine kinase activator activity / transmembrane receptor protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / response to cobalamin / Signaling by ERBB4 / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Respiratory syncytial virus (RSV) attachment and entry / 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 / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / positive regulation of DNA repair / regulation of ERK1 and ERK2 cascade / SHC1 events in ERBB2 signaling / ossification / cellular response to dexamethasone stimulus / neurogenesis / positive regulation of synaptic transmission, glutamatergic / positive regulation of epithelial cell proliferation / neuron projection morphogenesis / basal plasma membrane / epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / Signaling by ERBB2 TMD/JMD mutants / lung development / EGFR downregulation / positive regulation of smooth muscle cell proliferation / positive regulation of MAP kinase activity / Constitutive Signaling by EGFRvIII / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / kinase binding / Downregulation of ERBB2 signaling / positive regulation of miRNA transcription / peptidyl-tyrosine phosphorylation / cell-cell adhesion / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
Chem-QP7 / 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)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 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
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)151,70912
Polymers149,9174
Non-polymers1,7928
Water4,630257
1
D: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8556
Polymers74,9592
Non-polymers8964
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3450 Å2
ΔGint-40 kcal/mol
Surface area26520 Å2
MethodPISA
2
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8556
Polymers74,9592
Non-polymers8964
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3450 Å2
ΔGint-44 kcal/mol
Surface area26770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.100, 102.120, 87.380
Angle α, β, γ (deg.)90.000, 102.550, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 701 through 862 or resid 876...
21(chain B and (resid 701 through 862 or resid 876...
31(chain C and (resid 701 through 947 or resid 949 through 1101))
41(chain D and (resid 701 through 862 or resid 876...

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 862 or resid 876...AB701 - 8627 - 168
12VALVALMETMET(chain A and (resid 701 through 862 or resid 876...AB876 - 947182 - 253
13LYSLYSMETMET(chain A and (resid 701 through 862 or resid 876...AB949 - 1007255 - 313
14QP7QP7QP7QP7(chain A and (resid 701 through 862 or resid 876...AG1101
21GLNGLNLEULEU(chain B and (resid 701 through 862 or resid 876...BC701 - 8627 - 168
22VALVALMETMET(chain B and (resid 701 through 862 or resid 876...BC876 - 947182 - 253
23LYSLYSMETMET(chain B and (resid 701 through 862 or resid 876...BC949 - 1007255 - 313
24QP7QP7QP7QP7(chain B and (resid 701 through 862 or resid 876...BI1101
31GLNGLNMETMET(chain C and (resid 701 through 947 or resid 949 through 1101))CD701 - 9477 - 253
32LYSLYSQP7QP7(chain C and (resid 701 through 947 or resid 949 through 1101))CD - K949 - 1101255
41GLNGLNLEULEU(chain D and (resid 701 through 862 or resid 876...DA701 - 8627 - 168
42VALVALMETMET(chain D and (resid 701 through 862 or resid 876...DA876 - 947182 - 253
43LYSLYSMETMET(chain D and (resid 701 through 862 or resid 876...DA949 - 1007255 - 313
44QP7QP7QP7QP7(chain D and (resid 701 through 862 or resid 876...DE1101

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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-QP7 / 3-[4-(4-fluorophenyl)-5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-imidazol-2-yl]propan-1-ol


Mass: 412.459 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H21FN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 257 / 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: 2.07 Å3/Da / Density % sol: 40.45 %
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: 0.97918 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: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.4→52.16 Å / Num. obs: 47153 / % possible obs: 98.8 % / Redundancy: 6.9 % / CC1/2: 0.997 / Rmerge(I) obs: 0.122 / Rpim(I) all: 0.05 / Rrim(I) all: 0.132 / Net I/σ(I): 12.7 / Num. measured all: 323558 / Scaling rejects: 512
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.4-2.465.80.792002334320.7680.350.866297.6
10.73-52.166.70.03437865610.9990.0140.03737.398.6

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Processing

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

5d41


Resolution: 2.4→52.16 Å / SU ML: 0.36 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 28.91
RfactorNum. reflection% reflection
Rfree0.2435 2311 4.9 %
Rwork0.1915 --
obs0.194 47127 98.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 105.14 Å2 / Biso mean: 45.4973 Å2 / Biso min: 22.81 Å2
Refinement stepCycle: final / Resolution: 2.4→52.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9768 0 128 257 10153
Biso mean--43.16 43.71 -
Num. residues----1213
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A5798X-RAY DIFFRACTION19.663TORSIONAL
12B5798X-RAY DIFFRACTION19.663TORSIONAL
13C5798X-RAY DIFFRACTION19.663TORSIONAL
14D5798X-RAY DIFFRACTION19.663TORSIONAL
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 (%)
2.4-2.450.35071520.28812566271897
2.45-2.50.39751410.25772557269897
2.5-2.560.31491350.24992559269497
2.56-2.620.31111110.24132663277499
2.62-2.70.31441320.22722628276099
2.7-2.770.26191280.215826622790100
2.77-2.860.29681420.22432638278099
2.86-2.970.28951640.217926402804100
2.97-3.090.29691380.212726462784100
3.09-3.230.32521210.222726732794100
3.23-3.40.28021260.220226702796100
3.4-3.610.2841420.201926402782100
3.61-3.890.19721350.170926782813100
3.89-4.280.1791300.15632661279199
4.28-4.90.19291460.15292500264694
4.9-6.170.20271280.170827032831100
6.17-52.160.20281400.16672732287299

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