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- PDB-5x2f: Crystal structure of EGFR 696-1022 T790M/V948R in complex with SKLB(6) -

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Basic information

Entry
Database: PDB / ID: 5x2f
TitleCrystal structure of EGFR 696-1022 T790M/V948R in complex with SKLB(6)
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M / V948R / SKLB
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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / 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 / 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 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / ossification / SHC1 events in ERBB2 signaling / basal plasma membrane / positive regulation of DNA repair / cellular response to epidermal growth factor stimulus / positive regulation of DNA replication / epithelial cell proliferation / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / EGFR downregulation / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / cell-cell adhesion / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / positive regulation of fibroblast proliferation / cell morphogenesis / neuron differentiation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / cell junction / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / Cargo recognition for clathrin-mediated endocytosis / PIP3 activates AKT signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / virus receptor activity / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / 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 / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade
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-7XU / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.2 Å
AuthorsYun, C.H.
Funding support China, 3items
OrganizationGrant numberCountry
National Science Foundation of China31270769 China
National Basic Research Program of China2012CB917202 China
Ministry of Science and Technology of ChinaNCET-12-0013 China
CitationJournal: Oncotarget / Year: 2018
Title: Structural insights into drug development strategy targeting EGFR T790M/C797S.
Authors: Zhu, S.J. / Zhao, P. / Yang, J. / Ma, R. / Yan, X.E. / Yang, S.Y. / Yang, J.W. / Yun, C.H.
History
DepositionJan 31, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 7, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2018Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Apr 11, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,8298
Polymers150,8984
Non-polymers1,9304
Water6,846380
1
A: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,4144
Polymers75,4492
Non-polymers9652
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3040 Å2
ΔGint-19 kcal/mol
Surface area26870 Å2
MethodPISA
2
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,4144
Polymers75,4492
Non-polymers9652
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3080 Å2
ΔGint-22 kcal/mol
Surface area26530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.499, 102.593, 87.026
Angle α, β, γ (deg.)90.00, 102.64, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 37724.598 Da / Num. of mol.: 4 / Fragment: UNP RESIDUES 696-1022 / 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-7XU / 9-cyclohexyl-N2-[4-(4-methylpiperazin-1-yl)phenyl]-N8-phenyl-purine-2,8-diamine


Mass: 482.623 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H34N8
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 380 / 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: 2.06 Å3/Da / Density % sol: 40.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1M Bis-Tris 5.0, 22.5% PEG 3350, 5mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97924 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 6, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97924 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 55540 / % possible obs: 89.4 % / Redundancy: 3.2 % / Net I/σ(I): 8.9

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementResolution: 2.2→39.232 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.61
RfactorNum. reflection% reflection
Rfree0.2398 2833 5.1 %
Rwork0.2025 --
obs0.2044 55505 89.19 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.2→39.232 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9694 0 144 380 10218
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01410080
X-RAY DIFFRACTIONf_angle_d1.32513655
X-RAY DIFFRACTIONf_dihedral_angle_d20.0543815
X-RAY DIFFRACTIONf_chiral_restr0.1251519
X-RAY DIFFRACTIONf_plane_restr0.0131710
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.23790.28471050.27312283X-RAY DIFFRACTION76
2.2379-2.27860.31261230.27522329X-RAY DIFFRACTION79
2.2786-2.32240.32131470.26462326X-RAY DIFFRACTION80
2.3224-2.36980.25261170.2552380X-RAY DIFFRACTION81
2.3698-2.42140.3151160.25762384X-RAY DIFFRACTION81
2.4214-2.47770.2841230.26612391X-RAY DIFFRACTION81
2.4777-2.53960.30161230.2572407X-RAY DIFFRACTION82
2.5396-2.60830.27961220.25212427X-RAY DIFFRACTION83
2.6083-2.6850.29251360.23922492X-RAY DIFFRACTION84
2.685-2.77170.28641290.24672531X-RAY DIFFRACTION86
2.7717-2.87070.23361400.2342613X-RAY DIFFRACTION89
2.8707-2.98560.24531510.22822744X-RAY DIFFRACTION92
2.9856-3.12140.2791410.22212809X-RAY DIFFRACTION95
3.1214-3.28590.25711710.21132824X-RAY DIFFRACTION97
3.2859-3.49170.23571640.19622930X-RAY DIFFRACTION99
3.4917-3.76110.21081570.18092954X-RAY DIFFRACTION100
3.7611-4.13920.19591520.17022943X-RAY DIFFRACTION100
4.1392-4.73730.17781700.15342955X-RAY DIFFRACTION100
4.7373-5.96510.22131910.17492946X-RAY DIFFRACTION100
5.9651-39.2380.25481550.17653004X-RAY DIFFRACTION99

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