+Open data
-Basic information
Entry | Database: PDB / ID: 3w2q | ||||||
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Title | EGFR kinase domain T790M/L858R mutant with HKI-272 | ||||||
Components | Epidermal growth factor receptor | ||||||
Keywords | TRANSFERASE/TRANSFERASE INHIBITOR / ANTI-ONCOGENE / CELL CYCLE / DISEASE MUTATION / KINASE DOMAIN / RECEPTOR / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex | ||||||
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 / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB4 / eyelid development in camera-type eye / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Respiratory syncytial virus (RSV) attachment and entry / regulation of JNK cascade / : / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to cadmium ion / positive regulation of DNA repair / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / neurogenesis / regulation of ERK1 and ERK2 cascade / basal plasma membrane / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / epithelial cell proliferation / positive regulation of DNA replication / Signal transduction by L1 / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / lung development / positive regulation of MAP kinase activity / Constitutive Signaling by EGFRvIII / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / kinase binding / ruffle membrane / cell-cell adhesion / positive regulation of miRNA transcription Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å | ||||||
Authors | Sogabe, S. / Kawakita, Y. / Igaki, S. | ||||||
Citation | Journal: Acs Med.Chem.Lett. / Year: 2013 Title: Structure-Based Approach for the Discovery of Pyrrolo[3,2-d]pyrimidine-Based EGFR T790M/L858R Mutant Inhibitors. Authors: Sogabe, S. / Kawakita, Y. / Igaki, S. / Iwata, H. / Miki, H. / Cary, D.R. / Takagi, T. / Takagi, S. / Ohta, Y. / Ishikawa, T. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 3w2q.cif.gz | 142.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb3w2q.ent.gz | 111.1 KB | Display | PDB format |
PDBx/mmJSON format | 3w2q.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 3w2q_validation.pdf.gz | 715.7 KB | Display | wwPDB validaton report |
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Full document | 3w2q_full_validation.pdf.gz | 718 KB | Display | |
Data in XML | 3w2q_validation.xml.gz | 14.5 KB | Display | |
Data in CIF | 3w2q_validation.cif.gz | 19.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/w2/3w2q ftp://data.pdbj.org/pub/pdb/validation_reports/w2/3w2q | HTTPS FTP |
-Related structure data
Related structure data | 3w2oC 3w2pC 3w2rC 3w2sC 1m14S C: citing same article (ref.) S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 38020.969 Da / Num. of mol.: 1 / Fragment: Kinase domain, UNP residues 698-1022 / Mutation: T790M/L858R Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pFastBac1 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: P00533, receptor protein-tyrosine kinase |
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#2: Chemical | ChemComp-HKI / |
#3: Chemical | ChemComp-MES / |
#4: Water | ChemComp-HOH / |
Nonpolymer details | THE INHIBITOR HKI IS BOUND AT CYS 797 WITH A COVALENT BOND BETWEEN CBT OF HKI AND SG OF CYS. THE ...THE INHIBITOR HKI IS BOUND AT CYS 797 WITH A COVALENT BOND BETWEEN CBT OF HKI AND SG OF CYS. THE PRE-REACTION COMPOUND HAD A DOUBLE BOND BETWEEN CBT AND CAX WHICH OPENED UP TO FORM THE COVALENT LINKAGE WITH CYS SIDE CHAIN UPON REACTION. |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 3.28 Å3/Da / Density % sol: 62.5 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 Details: 0.1M Bis-tris propane pH 6.5, 35% Tacsimate, VAPOR DIFFUSION, SITTING DROP, temperature 293K |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97649 Å |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 9, 2008 |
Radiation | Monochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.97649 Å / Relative weight: 1 |
Reflection | Resolution: 2.2→50 Å / Num. obs: 24849 / % possible obs: 97.5 % / Redundancy: 4.3 % / Rsym value: 0.062 / Net I/σ(I): 20.5 |
Reflection shell | Resolution: 2.2→2.25 Å / Redundancy: 2 % / Mean I/σ(I) obs: 2.1 / Rsym value: 0.333 / % possible all: 76.5 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 1M14 Resolution: 2.2→40 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.949 / SU B: 7.718 / SU ML: 0.097 / Cross valid method: THROUGHOUT / ESU R: 0.177 / ESU R Free: 0.15 / Stereochemistry target values: MAXIMUM LIKELIHOOD
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK | |||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 43.406 Å2
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Refinement step | Cycle: LAST / Resolution: 2.2→40 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.197→2.254 Å / Total num. of bins used: 20
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Refinement TLS params. | Method: refined / Origin x: -7.9846 Å / Origin y: 24.7901 Å / Origin z: 57.4101 Å
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Refinement TLS group |
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