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

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Basic information

Entry
Database: PDB / ID: 6tfz
TitleCrystal Structure of EGFR T790M/V948R in Complex with Covalent Pyrrolopyrimidine 19
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-N7B / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 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 1.1Oct 7, 2020Group: Database references / Category: citation_author / Item: _citation_author.name
Revision 1.2Nov 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 / _citation_author.name
Revision 1.3Jan 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 1.4Nov 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)77,75812
Polymers75,9282
Non-polymers1,83010
Water3,927218
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8966
Polymers37,9641
Non-polymers9325
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8626
Polymers37,9641
Non-polymers8985
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.500, 82.500, 90.200
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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-N7B / ~{N}-[2-(2-hydroxyethyloxy)-5-[4-[[1-(phenylmethyl)indazol-5-yl]amino]-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]propanamide


Mass: 547.607 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H29N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 218 / 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: 2.31 Å3/Da / Density % sol: 46.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 30 % PEG3350, 100 mM MgSO4, 4 % ethylen glycole 7.5 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: 0.915 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 24, 2018
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.915 Å / Relative weight: 1
ReflectionResolution: 1.8→45.1 Å / Num. obs: 53054 / % possible obs: 99 % / Redundancy: 13.29 % / CC1/2: 1 / Rrim(I) all: 0.073 / Net I/σ(I): 20.25
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 14.02 % / Mean I/σ(I) obs: 2.51 / Num. unique obs: 7769 / CC1/2: 0.85 / Rrim(I) all: 1.055 / % possible all: 98.3

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5j9z

5j9z


Resolution: 1.8→45.1 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 20.21
RfactorNum. reflection% reflection
Rfree0.2065 2652 5 %
Rwork0.1741 --
obs0.1757 53043 99.01 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 95.09 Å2 / Biso mean: 34.9242 Å2 / Biso min: 16.12 Å2
Refinement stepCycle: final / Resolution: 1.8→45.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4183 0 143 218 4544
Biso mean--38.28 40.47 -
Num. residues----535
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.8-1.83270.29491360.2517257998
1.8327-1.8680.27631370.2337260398
1.868-1.90610.28531360.2071258998
1.9061-1.94760.22841360.1958260798
1.9476-1.99290.2661370.1781259899
1.9929-2.04270.25881380.1805262999
2.0427-2.09790.18771370.1705258999
2.0979-2.15970.21161390.1671264999
2.1597-2.22940.19761370.1733261198
2.2294-2.3090.22751400.1743264199
2.309-2.40150.22041390.1732264599
2.4015-2.51080.22851390.1794264399
2.5108-2.64310.23461400.18062659100
2.6431-2.80870.19581400.1824266099
2.8087-3.02550.19091410.18492675100
3.0255-3.32990.20321420.17612696100
3.3299-3.81160.21821420.16642709100
3.8116-4.80130.16041450.1442748100
4.8013-45.10.20431510.18512861100
Refinement TLS params.Method: refined / Origin x: -6.5784 Å / Origin y: 5.3908 Å / Origin z: 10.1417 Å
111213212223313233
T0.2145 Å20.0146 Å20.0053 Å2-0.151 Å20.0048 Å2--0.1527 Å2
L1.6456 °20.0766 °20.2715 °2-0.3384 °2-0.0915 °2--0.7434 °2
S-0.0382 Å °-0.0119 Å °-0.0672 Å °-0.0114 Å °0.014 Å °0.003 Å °0.0031 Å °-0.1268 Å °0.0246 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA701 - 982
2X-RAY DIFFRACTION1allB700 - 984
3X-RAY DIFFRACTION1allC1 - 2
4X-RAY DIFFRACTION1allD1 - 5
5X-RAY DIFFRACTION1allD6 - 7
6X-RAY DIFFRACTION1allS1 - 337
7X-RAY DIFFRACTION1allD8

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