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

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Basic information

Entry
Database: PDB / ID: 6tfy
TitleCrystal Structure of EGFR T790M/V948R in Complex with Covalent Pyrrolopyrimidine 18c
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / HER2 / EGFR / covalent Inhibitors
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-N7Z / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 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

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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)77,5549
Polymers75,9282
Non-polymers1,6267
Water3,783210
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7294
Polymers37,9641
Non-polymers7653
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8255
Polymers37,9641
Non-polymers8614
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.200, 82.800, 89.900
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 699 through 750 or resid 756...
21(chain B and (resid 699 through 700 or (resid 701...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 699 through 750 or resid 756...A699 - 750
121(chain A and (resid 699 through 750 or resid 756...A756 - 789
131(chain A and (resid 699 through 750 or resid 756...A791 - 801
141(chain A and (resid 699 through 750 or resid 756...A876 - 97
151(chain A and (resid 699 through 750 or resid 756...A876 - 975
161(chain A and (resid 699 through 750 or resid 756...A977 - 982
211(chain B and (resid 699 through 700 or (resid 701...B699 - 700
221(chain B and (resid 699 through 700 or (resid 701...B701 - 702
231(chain B and (resid 699 through 700 or (resid 701...B699 - 984
241(chain B and (resid 699 through 700 or (resid 701...B699 - 984
251(chain B and (resid 699 through 700 or (resid 701...B699 - 984
261(chain B and (resid 699 through 700 or (resid 701...B699 - 984

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Components

#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
#2: Chemical ChemComp-N7Z / ~{N}-[5-[4-[[3-chloranyl-4-(pyridin-2-ylmethoxy)phenyl]amino]-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]-2-(3-oxidanylpropoxy)phenyl]propanamide


Mass: 573.042 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H29ClN6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 210 / Source method: isolated from a natural source / Formula: H2O
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: 2.32 Å3/Da / Density % sol: 47.08 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 30 % PEG3350, 100 mM MgSO4, 3 % 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: 1.7→47.58 Å / Num. obs: 63198 / % possible obs: 99.9 % / Redundancy: 6.63 % / CC1/2: 0.999 / Rrim(I) all: 0.054 / Net I/σ(I): 15.99
Reflection shellResolution: 1.7→1.8 Å / Redundancy: 6.7 % / Mean I/σ(I) obs: 1.49 / Num. unique obs: 9820 / CC1/2: 0.728 / Rrim(I) all: 1.111 / % 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: 1.7→47.575 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 22.85
RfactorNum. reflection% reflection
Rfree0.2119 3158 5 %
Rwork0.1923 --
obs0.1933 63146 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 126.38 Å2 / Biso mean: 42.3012 Å2 / Biso min: 19.6 Å2
Refinement stepCycle: final / Resolution: 1.7→47.575 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4221 0 113 210 4544
Biso mean--41.75 45.3 -
Num. residues----530
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2440X-RAY DIFFRACTION8.108TORSIONAL
12B2440X-RAY DIFFRACTION8.108TORSIONAL
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.7-1.72540.40311350.362548
1.7254-1.75230.37771360.31942584
1.7523-1.78110.30291340.28572556
1.7811-1.81180.31421360.27212596
1.8118-1.84470.33031370.25122599
1.8447-1.88020.25051350.24372565
1.8802-1.91860.24951350.21842568
1.9186-1.96030.23031360.21372578
1.9603-2.00590.23131370.20862607
2.0059-2.05610.24841360.20882572
2.0561-2.11170.25311350.20872579
2.1117-2.17380.21071370.20442605
2.1738-2.2440.26011370.20182599
2.244-2.32420.24651360.20312585
2.3242-2.41720.25931370.20372586
2.4172-2.52720.2591370.20332615
2.5272-2.66050.21911380.20592620
2.6605-2.82710.2161380.19682623
2.8271-3.04540.23671390.19942632
3.0454-3.35180.23631380.19842626
3.3518-3.83660.18381390.17472650
3.8366-4.8330.14221420.15062689
4.833-47.570.19191480.18592806
Refinement TLS params.Method: refined / Origin x: -31.585 Å / Origin y: 5.0342 Å / Origin z: -10.5357 Å
111213212223313233
T0.2528 Å2-0.0077 Å2-0.0195 Å2-0.165 Å20.0074 Å2--0.1912 Å2
L2.643 °20.2831 °20.5749 °2-0.332 °20.2322 °2--1.2759 °2
S-0.0947 Å °0.012 Å °0.0492 Å °-0.0064 Å °0.0445 Å °0.0612 Å °-0.0005 Å °0.1986 Å °0.0408 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA699 - 982
2X-RAY DIFFRACTION1allE1001
3X-RAY DIFFRACTION1allC1 - 8
4X-RAY DIFFRACTION1allB699 - 984
5X-RAY DIFFRACTION1allE1002
6X-RAY DIFFRACTION1allD1 - 245

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