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- PDB-9gl8: EGFR Exon20 insertion mutant NPG bound with STX-721 -

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Basic information

Entry
Database: PDB / ID: 9gl8
TitleEGFR Exon20 insertion mutant NPG bound with STX-721
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Kinase / Inhibitor
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: 1.632 Å
AuthorsHilbert, B.J. / Brooijmans, N. / Milgram, B.C. / Pagliarini, R.A.
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 27, 2024Deposition site: PDBE / Processing site: PDBE
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)39,4676
Polymers38,6781
Non-polymers7895
Water6,738374
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area610 Å2
ΔGint-15 kcal/mol
Surface area15060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.291, 106.741, 175.21
Angle α, β, γ (deg.)90, 90, 90
Int Tables number20
Space group name H-MC2221

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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: 38677.609 Da / Num. of mol.: 1 / Mutation: V948R
Source method: isolated from a genetically manipulated source
Details: D770_N771insNPG / Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase

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Non-polymers , 5 types, 379 molecules

#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-A1IMT / (2R,3S)-3-[(3-chloranyl-2-methoxy-phenyl)amino]-2-[3-[2-[(2R)-1-[(E)-4-(dimethylamino)but-2-enoyl]-2-methyl-pyrrolidin-2-yl]ethynyl]pyridin-4-yl]-1,2,3,5,6,7-hexahydropyrrolo[3,2-c]pyridin-4-one


Mass: 589.128 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H37ClN6O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 374 / 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: 2.44 Å3/Da / Density % sol: 49.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2 M Potassium Chloride, 0.1 Magnesium Acetate, 0.05 M MES-NaOH pH 6.5, 10% w/v PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.965459 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: May 17, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.965459 Å / Relative weight: 1
ReflectionResolution: 1.63→34.626 Å / Num. obs: 35208 / % possible obs: 92.6 % / Redundancy: 13.09 % / CC1/2: 0.998 / Rmerge(I) obs: 0.0997 / Rpim(I) all: 0.0286 / Rrim(I) all: 0.1038 / Net I/σ(I): 13.48
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
3.968-34.62612.470.059435.1235210.9970.01760.0621100
3.126-3.96813.260.064930.6435210.9980.01840.0675100
2.721-3.12613.230.096621.6335200.9980.02740.1004100
2.468-2.72113.290.146214.9235210.9960.04120.152100
2.287-2.46813.20.205710.9235210.9930.05830.2139100
2.15-2.28713.480.29428.1735210.9870.08210.3056100
2.039-2.1513.290.46125.335210.9780.12990.4794100
1.948-2.03913.360.72573.5535200.9510.20380.754198.8
1.852-1.94813.651.04722.635210.9180.29271.087781.7
1.632-1.85211.681.18331.9835210.8150.35641.237863.5

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROC1.1.7 20230222data processing
XDSJan 10, 2022data reduction
Aimless0.7.9data scaling
STARANISO2.3.92data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.632→34.626 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.931 / SU R Cruickshank DPI: 0.16 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.131 / SU Rfree Blow DPI: 0.123 / SU Rfree Cruickshank DPI: 0.117
RfactorNum. reflection% reflectionSelection details
Rfree0.2244 1671 -RANDOM
Rwork0.1867 ---
obs0.1885 35208 74 %-
Displacement parametersBiso mean: 33.15 Å2
Baniso -1Baniso -2Baniso -3
1-0.091 Å20 Å20 Å2
2--1.2626 Å20 Å2
3----1.3536 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 1.632→34.626 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2482 0 54 374 2910
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015222HARMONIC2
X-RAY DIFFRACTIONt_angle_deg19459HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1566SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes799HARMONIC5
X-RAY DIFFRACTIONt_it2646HARMONIC10
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_chiral_improper_torsion332SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4794SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.42
X-RAY DIFFRACTIONt_other_torsion14.93
LS refinement shellResolution: 1.632→1.72 Å
RfactorNum. reflection% reflection
Rfree0.292 32 -
Rwork0.275 --
obs--10.68 %
Refinement TLS params.Origin x: 1.8356 Å / Origin y: 14.6036 Å / Origin z: -19.2087 Å
111213212223313233
T0.0082 Å20.006 Å2-0.0015 Å2--0.0191 Å20.0165 Å2---0.0137 Å2
L0.0611 °2-0.243 °20.0653 °2-0.5763 °20.0265 °2--1.5544 °2
S-0.11 Å °0.1857 Å °-0.0131 Å °0.1857 Å °0.0336 Å °0.0345 Å °-0.0131 Å °0.0345 Å °0.0764 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A701 - 1021
2X-RAY DIFFRACTION1{ A|* }A1031 - 2001

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