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- PDB-5hg8: EGFR (L858R, T790M, V948R) in complex with N-[3-({2-[(1-methyl-1H... -

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Basic information

Entry
Database: PDB / ID: 5hg8
TitleEGFR (L858R, T790M, V948R) in complex with N-[3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)phenyl]prop-2-enamide
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / EGFR / Kinase / Inhibitor / Lung Cancer / 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 / regulation of nitric-oxide synthase activity / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / 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 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signaling by ERBB4 / 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 / 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 / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / positive regulation of DNA replication / positive regulation of bone resorption / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / regulation of peptidyl-tyrosine phosphorylation / peptidyl-tyrosine autophosphorylation / positive regulation of vasoconstriction / positive regulation of glial cell proliferation / positive regulation of phosphorylation / 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 / neurogenesis / transmembrane receptor protein tyrosine kinase activity / ossification / cellular response to dexamethasone stimulus / SHC1 events in ERBB2 signaling / 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 / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / clathrin-coated endocytic vesicle membrane / lung development / positive regulation of smooth muscle cell proliferation / 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-634 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.42 Å
AuthorsGajiwala, K.S.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT ...Title: Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants.
Authors: Cheng, H. / Nair, S.K. / Murray, B.W. / Almaden, C. / Bailey, S. / Baxi, S. / Behenna, D. / Cho-Schultz, S. / Dalvie, D. / Dinh, D.M. / Edwards, M.P. / Feng, J.L. / Ferre, R.A. / Gajiwala, K. ...Authors: Cheng, H. / Nair, S.K. / Murray, B.W. / Almaden, C. / Bailey, S. / Baxi, S. / Behenna, D. / Cho-Schultz, S. / Dalvie, D. / Dinh, D.M. / Edwards, M.P. / Feng, J.L. / Ferre, R.A. / Gajiwala, K.S. / Hemkens, M.D. / Jackson-Fisher, A. / Jalaie, M. / Johnson, T.O. / Kania, R.S. / Kephart, S. / Lafontaine, J. / Lunney, B. / Liu, K.K. / Liu, Z. / Matthews, J. / Nagata, A. / Niessen, S. / Ornelas, M.A. / Orr, S.T. / Pairish, M. / Planken, S. / Ren, S. / Richter, D. / Ryan, K. / Sach, N. / Shen, H. / Smeal, T. / Solowiej, J. / Sutton, S. / Tran, K. / Tseng, E. / Vernier, W. / Walls, M. / Wang, S. / Weinrich, S.L. / Xin, S. / Xu, H. / Yin, M.J. / Zientek, M. / Zhou, R. / Kath, J.C.
History
DepositionJan 8, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 3, 2016Provider: repository / Type: Initial release
Revision 1.1Feb 10, 2016Group: Database references
Revision 1.2Mar 23, 2016Group: Database references
Revision 1.3Nov 22, 2017Group: Database references / Derived calculations / Refinement description
Category: citation / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.4Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2425
Polymers37,5801
Non-polymers6624
Water3,765209
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.932, 69.730, 110.610
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 37580.453 Da / Num. of mol.: 1 / Fragment: UNP residues 695-1022 / Mutation: L858R, 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-634 / N-[3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)phenyl]propanamide / Bound form of N-[3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)phenyl]prop-2-enamide


Mass: 377.400 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19N7O2
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 209 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsThe 634 ligand represent bound form of N-[3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d] ...The 634 ligand represent bound form of N-[3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)phenyl]prop-2-enamide which has a double bond between C20 and C21 atom group.

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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: 2.05 Å3/Da / Density % sol: 39.97 %
Crystal growTemperature: 286 K / Method: vapor diffusion, sitting drop
Details: 0.1 M (5.0 uL of stock 1.0 M) HEPES (pH 7.50), 0.2 M (2.8571428571 uL of stock 3.5 M) Ammonium sulfate, 20.0 %w/v (20.0 uL of stock 50.0 %w/v) PEG 8000, 10.0 %v/v (5.0 uL of stock 100.0 %v/v) iso-propanol

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 19, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.42→58.99 Å / Num. obs: 58632 / % possible obs: 100 % / Redundancy: 6.3 % / Biso Wilson estimate: 18 Å2 / Rsym value: 0.064 / Net I/σ(I): 15
Reflection shellResolution: 1.42→1.5 Å / Redundancy: 6.4 % / Rmerge(I) obs: 0.49 / Mean I/σ(I) obs: 2.9 / % possible all: 100

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Processing

Software
NameVersionClassification
CNX2005refinement
SCALAdata scaling
autoPROCdata scaling
RefinementResolution: 1.42→58.99 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 1173784.01 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.213 2761 4.7 %RANDOM
Rwork0.208 ---
obs0.208 58555 98.9 %-
all-58858 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 39.3485 Å2 / ksol: 0.380685 e/Å3
Displacement parametersBiso mean: 21.2 Å2
Baniso -1Baniso -2Baniso -3
1-8.43 Å20 Å20 Å2
2---3.34 Å20 Å2
3----5.1 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.18 Å0.17 Å
Luzzati d res low-5 Å
Luzzati sigma a0.15 Å0.17 Å
Refinement stepCycle: 1 / Resolution: 1.42→58.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2491 0 16 209 2716
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d18.8
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.64
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.151.5
X-RAY DIFFRACTIONc_mcangle_it1.782
X-RAY DIFFRACTIONc_scbond_it2.072
X-RAY DIFFRACTIONc_scangle_it3.032.5
LS refinement shellResolution: 1.42→1.51 Å / Rfactor Rfree error: 0.015 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.293 385 4.2 %
Rwork0.294 8710 -
obs--93.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep-edited.paramprotein-edited.top
X-RAY DIFFRACTION2ACCELRYS_CNX:libraries/toppar/dna-rna_rep.paraACCELRYS_CNX:libraries/toppar/dna-rna.top
X-RAY DIFFRACTION3ACCELRYS_CNX:libraries/toppar/water_rep.paramACCELRYS_CNX:libraries/toppar/water.top
X-RAY DIFFRACTION4ACCELRYS_CNX:libraries/toppar/ion.paramACCELRYS_CNX:libraries/toppar/ion.top

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