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- PDB-9fqs: EGFR Exon20 insertion mutant NPG bound with Compound 39 -

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Basic information

Entry
Database: PDB / ID: 9fqs
TitleEGFR Exon20 insertion mutant NPG bound with Compound 39
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Kinase / inhibitor
Function / homology
Function and homology information


multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / morphogenesis of an epithelial fold / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / digestive tract morphogenesis / epidermal growth factor receptor activity / epidermal growth factor binding ...multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / morphogenesis of an epithelial fold / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / digestive tract morphogenesis / epidermal growth factor receptor activity / epidermal growth factor binding / response to UV-A / ubiquitin-dependent endocytosis / regulation of peptidyl-tyrosine phosphorylation / PLCG1 events in ERBB2 signaling / salivary gland morphogenesis / cerebral cortex cell migration / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / eyelid development in camera-type eye / ERBB2 Activates PTK6 Signaling / hair follicle development / Signaling by EGFR / embryonic placenta development / intracellular vesicle / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / negative regulation of epidermal growth factor receptor signaling pathway / protein insertion into membrane / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / epithelial cell proliferation / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / GAB1 signalosome / xenobiotic transport / positive regulation of G1/S transition of mitotic cell cycle / ossification / positive regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / positive regulation of epithelial cell proliferation / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / basal plasma membrane / positive regulation of DNA replication / positive regulation of DNA repair / cellular response to amino acid stimulus / Signal transduction by L1 / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / positive regulation of protein localization to plasma membrane / sperm principal piece / sperm end piece / positive regulation of fibroblast proliferation / clathrin-coated endocytic vesicle membrane / NOTCH3 Activation and Transmission of Signal to the Nucleus / negative regulation of protein catabolic process / cell-cell adhesion / Signaling by ERBB2 TMD/JMD mutants / cell morphogenesis / EGFR downregulation / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / cell junction / positive regulation of miRNA transcription / positive regulation of protein phosphorylation / gene expression / epidermal growth factor receptor signaling pathway / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / HCMV Early Events / sperm midpiece / positive regulation of canonical Wnt signaling pathway / actin filament binding / PIP3 activates AKT signaling / transmembrane signaling receptor activity / positive regulation of cell growth / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / nuclear membrane / RAF/MAP kinase cascade / protein tyrosine kinase activity
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 / 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: 1.783 Å
AuthorsHilbert, B.J. / Brooijmans, N. / Milgram, B.C. / Pagliarini, R.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of STX-721, a Covalent, Potent, and Highly Mutant-Selective EGFR/HER2 Exon20 Insertion Inhibitor for the Treatment of Non-Small Cell Lung Cancer.
Authors: Milgram, B.C. / Borrelli, D.R. / Brooijmans, N. / Henderson, J.A. / Hilbert, B.J. / Huff, M.R. / Ito, T. / Jackson, E.L. / Jonsson, P. / Ladd, B. / O'Hearn, E.L. / Pagliarini, R.A. / ...Authors: Milgram, B.C. / Borrelli, D.R. / Brooijmans, N. / Henderson, J.A. / Hilbert, B.J. / Huff, M.R. / Ito, T. / Jackson, E.L. / Jonsson, P. / Ladd, B. / O'Hearn, E.L. / Pagliarini, R.A. / Roberts, S.A. / Ronseaux, S. / Stuart, D.D. / Wang, W. / Guzman-Perez, A.
History
DepositionJun 17, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3034
Polymers38,6781
Non-polymers6263
Water4,900272
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area410 Å2
ΔGint7 kcal/mol
Surface area15000 Å2
Unit cell
Length a, b, c (Å)40.11, 106.51, 175.751
Angle α, β, γ (deg.)90, 90, 90
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-1418-

HOH

21A-1419-

HOH

31A-1444-

HOH

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Components

#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 D770_N771insNPG
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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-A1IE0 / 3-[(3-fluoranyl-2-methoxy-phenyl)amino]-2-[3-[2-[(2R)-1-propanoylpyrrolidin-2-yl]ethynyl]pyridin-4-yl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one / 3-[(3-fluoranyl-2-methoxy-phenyl)amino]-2-[3-[2-[(2R)-1-prop-2-enoylpyrrolidin-2-yl]ethynyl]pyridin-4-yl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (reacted form)


Mass: 501.552 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H28FN5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 272 / Source method: isolated from a natural source / Formula: H2O
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: 2.43 Å3/Da / Density % sol: 49.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.8
Details: 0.2 M Ammonium Sulfate, 100 mM HEPES-NaOH pH 6.8, 20% v/v PEG 5000 MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.97628 Å
DetectorType: DECTRIS EIGER2 X CdTe 16M / Detector: PIXEL / Date: May 30, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97628 Å / Relative weight: 1
ReflectionResolution: 1.783→34.52 Å / Num. obs: 27685 / % possible obs: 91.6 % / Redundancy: 13.28 % / CC1/2: 0.998 / Rmerge(I) obs: 0.1159 / Rpim(I) all: 0.0329 / Rrim(I) all: 0.1206 / Net I/σ(I): 12.67
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. measured obsNum. unique allNum. unique obsCC1/2CC1/2 anomalousRpim(I) allRrim(I) allAbsDiff over sigma anomalous% possible anomalous% possible ellipsoidal% possible ellipsoidal anomalous% possible spherical% possible spherical anomalousRedundancy anomalous% possible all
4.305-34.51912.790.058433.43540235402276927690.998-0.4350.01670.06080.5321001001001001007.19100
3.39-4.30313.260.063929.893671036710276827680.997-0.4790.01810.06640.6181001001001001007.11100
2.952-3.3913.330.098820.583691136911276927690.996-0.2180.02810.10280.72310099.910099.91007.0899.9
2.673-2.95213.60.157714.123764137641276827680.993-0.1350.04420.16390.7191001001001001007.17100
2.477-2.67313.640.24329.863775737757276927690.989-0.1260.0680.25270.6931001001001001007.15100
2.33-2.47713.530.38986.673745337453276827680.979-0.020.10960.40510.7061001001001001007.07100
2.21-2.3313.470.59054.873730337303276927690.984-0.0570.16630.61390.7211001001001001007.04100
2.109-2.2113.650.91573.33778037780276827680.8920.030.2560.95140.7397.997.297.997.297.97.197.2
2.008-2.10913.61.34452.373764737647276927690.814-0.0020.3771.39710.71585.485.385.480.180.77.0285.3
1.783-2.00811.971.78351.643314433144276827680.620.0150.531.86220.7225758.25725.624.96.2558.2

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Processing

Software
NameVersionClassification
autoPROC1.1.7 20240123data processing
XDSJan 10, 2022data reduction
Aimless0.7.15data scaling
STARANISO2.4.9data scaling
PHASER2.8.3phasing
BUSTER2.11.8refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.783→34.52 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.927 / SU R Cruickshank DPI: 0.261 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.173 / SU Rfree Blow DPI: 0.153 / SU Rfree Cruickshank DPI: 0.148
RfactorNum. reflection% reflectionSelection details
Rfree0.2368 1298 -RANDOM
Rwork0.1967 ---
obs0.1985 27685 75.8 %-
Displacement parametersBiso mean: 37.52 Å2
Baniso -1Baniso -2Baniso -3
1--0.4487 Å20 Å20 Å2
2--1.1976 Å20 Å2
3----0.7489 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 1.783→34.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2456 0 45 272 2773
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015175HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.029385HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1549SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes790HARMONIC5
X-RAY DIFFRACTIONt_it2616HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion330SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4490SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.33
X-RAY DIFFRACTIONt_other_torsion15.83
LS refinement shellResolution: 1.783→1.89 Å
RfactorNum. reflection% reflection
Rfree0.3192 24 -
Rwork0.2749 --
obs--9.55 %
Refinement TLS params.Origin x: -1.9775 Å / Origin y: -14.3237 Å / Origin z: -19.2381 Å
111213212223313233
T-0.0106 Å20.0077 Å20.0029 Å2--0.0238 Å2-0.0073 Å2---0.0142 Å2
L0.1599 °2-0.1237 °2-0.1069 °2-0.4665 °2-0.0241 °2--1.6858 °2
S-0.0686 Å °0.1616 Å °-0.0081 Å °0.1616 Å °0.0378 Å °-0.0329 Å °-0.0081 Å °-0.0329 Å °0.0308 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A701 - 1019
2X-RAY DIFFRACTION1{ A|* }A1101 - 2001

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