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- PDB-9df4: EGFR Exon20 insertion mutant SVD bound with STX-721 -

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Basic information

Entry
Database: PDB / ID: 9df4
TitleEGFR Exon20 insertion mutant SVD bound with STX-721
ComponentsEpidermal growth factor receptor
KeywordsONCOPROTEIN / TRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma ...positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / response to cobalamin / 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 / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of bone resorption / embryonic placenta development / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of peptidyl-serine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / basal plasma membrane / Signal transduction by L1 / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / cellular response to estradiol stimulus / lung development / EGFR downregulation / synaptic membrane / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / Constitutive Signaling by EGFRvIII / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / Signaling by ERBB2 ECD mutants
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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.78 Å
AuthorsHilbert, B.J. / Brooijmans, N. / Pagliarini, R.A. / Milgram, B.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Clin.Cancer Res. / Year: 2025
Title: STX-721, a Covalent EGFR/HER2 Exon 20 Inhibitor, Utilizes Exon 20-Mutant Dynamic Protein States and Achieves Unique Mutant Selectivity Across Human Cancer Models.
Authors: Pagliarini, R.A. / Henderson, J.A. / Milgram, B.C. / Borrelli, D.R. / Brooijmans, N. / Hilbert, B.J. / Huff, M.R. / Ito, T. / Kryukov, G.V. / Ladd, B. / Martin, B.R. / Motiwala, H. / ...Authors: Pagliarini, R.A. / Henderson, J.A. / Milgram, B.C. / Borrelli, D.R. / Brooijmans, N. / Hilbert, B.J. / Huff, M.R. / Ito, T. / Kryukov, G.V. / Ladd, B. / Martin, B.R. / Motiwala, H. / O'Hearn, E. / Tsai, C.F. / Wang, W. / Bellier, J. / Boland, L. / Clark, S. / Hensley, E. / Hata, A.N. / Kuzmic, P. / Guzman-Perez, A. / Jackson, E.L. / Stuart, D.D.
History
DepositionAug 29, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 14, 2025Provider: repository / Type: Initial release
Revision 1.1Jun 11, 2025Group: 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.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)40,07325
Polymers37,8651
Non-polymers2,20824
Water3,927218
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: Includes mutation known to prevent dimerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.020, 104.870, 176.630
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-1278-

HOH

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 37864.672 Da / Num. of mol.: 1 / Mutation: V951R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase

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Non-polymers , 5 types, 242 molecules

#2: Chemical ChemComp-A1A4E / (2P)-3-(3-chloro-2-methoxyanilino)-2-[3-({(2R)-1-[(2E)-4-(dimethylamino)but-2-enoyl]-2-methylpyrrolidin-2-yl}ethynyl)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one


Mass: 587.112 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H35ClN6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 218 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.45 Å3/Da / Density % sol: 49.74 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 0.8 microliters of 5.9 mg/mL was mixed 1:1 with 600 mM NaCl, 100 mM MES pH 6.2, and 16%W/V PEG4000. 0.2 microliters of a 10 mM Taurine solution was then added to the drop

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 30, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.78→45.13 Å / Num. obs: 36167 / % possible obs: 99.8 % / Redundancy: 12.1 % / CC1/2: 0.998 / Rmerge(I) obs: 0.088 / Rpim(I) all: 0.026 / Rrim(I) all: 0.092 / Χ2: 1 / Net I/σ(I): 15.9
Reflection shellResolution: 1.78→1.82 Å / % possible obs: 96.1 % / Redundancy: 8 % / Rmerge(I) obs: 0.837 / Num. measured all: 15900 / Num. unique obs: 1992 / CC1/2: 0.874 / Rpim(I) all: 0.307 / Rrim(I) all: 0.895 / Χ2: 0.81 / Net I/σ(I) obs: 2.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.78→45.13 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.965 / SU B: 2.354 / SU ML: 0.072 / Cross valid method: THROUGHOUT / ESU R: 0.106 / ESU R Free: 0.103 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1977 1817 5 %RANDOM
Rwork0.16585 ---
obs0.16748 34349 99.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 36.171 Å2
Baniso -1Baniso -2Baniso -3
1--0.4 Å20 Å2-0 Å2
2--2.4 Å2-0 Å2
3----2 Å2
Refinement stepCycle: 1 / Resolution: 1.78→45.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2483 0 142 218 2843
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0122685
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162639
X-RAY DIFFRACTIONr_angle_refined_deg1.4421.8633604
X-RAY DIFFRACTIONr_angle_other_deg0.8011.7826094
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9695313
X-RAY DIFFRACTIONr_dihedral_angle_2_deg5.445517
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.72410478
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0720.2397
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022995
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02568
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.5833.571240
X-RAY DIFFRACTIONr_mcbond_other2.583.5711240
X-RAY DIFFRACTIONr_mcangle_it3.8056.3931548
X-RAY DIFFRACTIONr_mcangle_other3.8046.3981549
X-RAY DIFFRACTIONr_scbond_it3.3754.0441445
X-RAY DIFFRACTIONr_scbond_other3.3744.0471446
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.2557.1892054
X-RAY DIFFRACTIONr_long_range_B_refined8.02137.253097
X-RAY DIFFRACTIONr_long_range_B_other7.94237.143038
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.78→1.826 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 126 -
Rwork0.269 2457 -
obs--96.92 %

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