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- PDB-6tfv: Crystal Structure of EGFR T790M/V948R in Complex with Covalent Py... -

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Basic information

Entry
Database: PDB / ID: 6tfv
TitleCrystal Structure of EGFR T790M/V948R in Complex with Covalent Pyrrolopyrimidine 18b
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / HER2 / EGFR / covalent Inhibitors
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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-N7Q / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsNiggenaber, J. / Mueller, M.P. / Rauh, D.
Funding support Germany, 3items
OrganizationGrant numberCountry
German Federal Ministry for Education and ResearchBMBF 01GS08104 Germany
German Federal Ministry for Education and ResearchBMBF 01ZX1303C Germany
European Regional Development FundEFRE-800400 Germany
CitationJournal: J.Med.Chem. / Year: 2020
Title: Targeting Her2-insYVMA with Covalent Inhibitors-A Focused Compound Screening and Structure-Based Design Approach.
Authors: Lategahn, J. / Hardick, J. / Grabe, T. / Niggenaber, J. / Jeyakumar, K. / Keul, M. / Tumbrink, H.L. / Becker, C. / Hodson, L. / Kirschner, T. / Klovekorn, P. / Ketzer, J. / Baumann, M. / ...Authors: Lategahn, J. / Hardick, J. / Grabe, T. / Niggenaber, J. / Jeyakumar, K. / Keul, M. / Tumbrink, H.L. / Becker, C. / Hodson, L. / Kirschner, T. / Klovekorn, P. / Ketzer, J. / Baumann, M. / Terheyden, S. / Unger, A. / Weisner, J. / Muller, M.P. / van Otterlo, W.A.L. / Bauer, S. / Rauh, D.
History
DepositionNov 14, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 30, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jan 24, 2024Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,65212
Polymers75,9282
Non-polymers1,72410
Water4,522251
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8396
Polymers37,9641
Non-polymers8755
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8136
Polymers37,9641
Non-polymers8495
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.400, 82.600, 89.900
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 37963.910 Da / Num. of mol.: 2 / Mutation: T790M, V948R
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 , 5 types, 261 molecules

#2: Chemical ChemComp-N7Q / ~{N}-[5-[4-[[3-chloranyl-4-(pyridin-2-ylmethoxy)phenyl]amino]-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]-2-(2-hydroxyethyloxy)phenyl]propanamide


Mass: 559.015 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H27ClN6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 251 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.3 Å3/Da / Density % sol: 46.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 27.5 % PEG3350, 100 mM MgSO4, 4 % ethylen glycole 7.0 mg/mL EGFR T790M/V948R (in 100 mM NaCl, 25 mM Tris-HCl, 10 % glycerol, 1 mM TCEP, pH 8.0) 1 ul reservoir + 1 ul protein solution)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 24, 2018
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.5→47.59 Å / Num. obs: 91525 / % possible obs: 100 % / Redundancy: 6.6 % / CC1/2: 0.999 / Rrim(I) all: 0.06 / Net I/σ(I): 15.91
Reflection shellResolution: 1.5→1.6 Å / Redundancy: 6.66 % / Mean I/σ(I) obs: 2.43 / Num. unique obs: 15883 / CC1/2: 0.843 / Rrim(I) all: 0.725 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5j9z

5j9z


Resolution: 1.5→47.586 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 19.36
RfactorNum. reflection% reflection
Rfree0.2028 4577 5 %
Rwork0.1827 --
obs0.1837 91517 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 72.07 Å2 / Biso mean: 28.7298 Å2 / Biso min: 12.03 Å2
Refinement stepCycle: final / Resolution: 1.5→47.586 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4248 0 131 251 4630
Biso mean--26.12 34.42 -
Num. residues----537
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.5-1.51710.28411490.25972832
1.5171-1.53490.28511510.25182853
1.5349-1.55360.24531510.2372876
1.5536-1.57330.25691510.23212857
1.5733-1.5940.2741510.21752879
1.594-1.61580.26111500.20682857
1.6158-1.63890.24461520.20762878
1.6389-1.66340.22281510.21022868
1.6634-1.68940.20111500.19392858
1.6894-1.71710.21671520.19542879
1.7171-1.74670.23881500.19182857
1.7467-1.77840.2041520.18352886
1.7784-1.81260.19921520.18792891
1.8126-1.84960.21751520.17992883
1.8496-1.88990.19931500.18392849
1.8899-1.93380.1961520.17422891
1.9338-1.98220.19261520.17672892
1.9822-2.03580.2031520.18152890
2.0358-2.09570.19931520.17952876
2.0957-2.16330.20751520.18052897
2.1633-2.24070.19871540.17722915
2.2407-2.33040.20921520.18242901
2.3304-2.43640.23311530.17932898
2.4364-2.56490.18591540.18672931
2.5649-2.72550.21711530.18972909
2.7255-2.9360.20411550.19452932
2.936-3.23140.21211540.19042925
3.2314-3.69880.19481560.18212967
3.6988-4.65950.17721570.15412986
4.6595-47.580.18751650.1793127
Refinement TLS params.Method: refined / Origin x: -31.935 Å / Origin y: 5.3466 Å / Origin z: -10.4565 Å
111213212223313233
T0.158 Å2-0.0072 Å20.0038 Å2-0.1118 Å2-0.0014 Å2--0.1191 Å2
L1.4412 °2-0.0149 °20.1834 °2-0.299 °20.0607 °2--0.8671 °2
S-0.0316 Å °-0.0333 Å °-0.0615 Å °0.0091 Å °0.0115 Å °-0.0037 Å °0.0335 Å °0.1446 Å °0.02 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA700 - 985
2X-RAY DIFFRACTION1allE1001
3X-RAY DIFFRACTION1allC1101 - 111
4X-RAY DIFFRACTION1allB698 - 984
5X-RAY DIFFRACTION1allE1002
6X-RAY DIFFRACTION1allD2 - 416

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