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- PDB-5gty: Crystal structure of EGFR 696-1022 T790M in complex with LXX-6-26 -

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Basic information

Entry
Database: PDB / ID: 5gty
TitleCrystal structure of EGFR 696-1022 T790M in complex with LXX-6-26
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M / LXX-6-26 / inhibitor
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / 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 prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / 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 / response to UV-A / epidermal growth factor binding / PLCG1 events in ERBB2 signaling / tongue development / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / regulation of nitric-oxide synthase activity / ERBB2 Activates PTK6 Signaling / morphogenesis of an epithelial fold / intracellular vesicle / Signaling by EGFR / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / Signaling by ERBB4 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein insertion into membrane / eyelid development in camera-type eye / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / activation of phospholipase C activity / positive regulation of cyclin-dependent protein serine/threonine kinase activity / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / positive regulation of bone resorption / positive regulation of DNA replication / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / regulation of peptidyl-tyrosine phosphorylation / peptidyl-tyrosine autophosphorylation / positive regulation of glial cell proliferation / positive regulation of phosphorylation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / positive regulation of DNA repair / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / cellular response to dexamethasone stimulus / SHC1 events in ERBB2 signaling / ossification / positive regulation of synaptic transmission, glutamatergic / basal plasma membrane / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / Signal transduction by L1 / epithelial cell proliferation / cellular response to estradiol stimulus / liver regeneration / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / clathrin-coated endocytic vesicle membrane / positive regulation of smooth muscle cell proliferation / lung development / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / positive regulation of MAP kinase activity / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / cell-cell adhesion / receptor protein-tyrosine kinase / ruffle membrane / Downregulation of ERBB2 signaling / kinase binding
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-816 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.14 Å
AuthorsYan, X.E. / Yun, C.H.
CitationJournal: Oncotarget / Year: 2017
Title: Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode.
Authors: Hu, C. / Wang, A. / Wu, H. / Qi, Z. / Li, X. / Yan, X.E. / Chen, C. / Yu, K. / Zou, F. / Wang, W. / Wang, W. / Wu, J. / Liu, J. / Wang, B. / Wang, L. / Ren, T. / Zhang, S. / Yun, C.H. / Liu, J. / Liu, Q.
History
DepositionAug 23, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 6, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 1.2Nov 29, 2017Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Nov 8, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
D: Epidermal growth factor receptor
E: Epidermal growth factor receptor
F: Epidermal growth factor receptor
G: Epidermal growth factor receptor
H: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)305,48520
Polymers301,2058
Non-polymers4,28012
Water5,459303
1
A: Epidermal growth factor receptor
E: Epidermal growth factor receptor
H: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,80511
Polymers150,6024
Non-polymers2,2027
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
D: Epidermal growth factor receptor
F: Epidermal growth factor receptor
G: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,6809
Polymers150,6024
Non-polymers2,0785
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)117.427, 71.796, 152.530
Angle α, β, γ (deg.)90.00, 103.53, 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: 37650.598 Da / Num. of mol.: 8 / Fragment: UNP RESIDUES 696-1022
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-816 / 1-[(3R)-3-[4-azanyl-3-[3-chloranyl-4-[(6-methylpyridin-2-yl)methoxy]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one


Mass: 503.983 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C26H26ClN7O2
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 303 / 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: 2.08 Å3/Da / Density % sol: 40.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 0.05M CaCl2, 0.1M B-Tris pH 6.2, 24% PEG 550MME, 5mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97776 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97776 Å / Relative weight: 1
ReflectionResolution: 3.15→50 Å / Num. obs: 42443 / % possible obs: 98.2 % / Redundancy: 5.1 % / Net I/σ(I): 6.14
Reflection shellResolution: 3.15→3.26 Å

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Processing

Software
NameVersionClassification
PHENIX(dev_2400)refinement
DENZOdata reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2JIT

2jit


Resolution: 3.14→49.81 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.97 / Phase error: 34.54 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2795 2094 5.04 %
Rwork0.2566 --
obs0.2578 41554 95.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.14→49.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms18649 0 304 303 19256
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0119400
X-RAY DIFFRACTIONf_angle_d1.34226317
X-RAY DIFFRACTIONf_dihedral_angle_d28.2147344
X-RAY DIFFRACTIONf_chiral_restr0.0872955
X-RAY DIFFRACTIONf_plane_restr0.0133290
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1402-3.21330.34681410.29252121X-RAY DIFFRACTION79
3.2133-3.29360.33791240.30482548X-RAY DIFFRACTION92
3.2936-3.38270.32591320.2772577X-RAY DIFFRACTION94
3.3827-3.48220.30391240.26882591X-RAY DIFFRACTION94
3.4822-3.59450.32621350.26082596X-RAY DIFFRACTION94
3.5945-3.7230.32071380.26042596X-RAY DIFFRACTION95
3.723-3.8720.29251430.24972643X-RAY DIFFRACTION97
3.872-4.04810.24671270.22832718X-RAY DIFFRACTION97
4.0481-4.26140.22531490.21532679X-RAY DIFFRACTION98
4.2614-4.52830.231340.21752748X-RAY DIFFRACTION99
4.5283-4.87760.26731550.23442704X-RAY DIFFRACTION98
4.8776-5.3680.25891720.24332690X-RAY DIFFRACTION99
5.368-6.14350.26361260.2692789X-RAY DIFFRACTION99
6.1435-7.73550.28611460.29592777X-RAY DIFFRACTION99
7.7355-49.81670.2961480.28942683X-RAY DIFFRACTION93

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