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- PDB-9nj7: Almonertinib in complex with WT EGFR -

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Basic information

Entry
Database: PDB / ID: 9nj7
TitleAlmonertinib in complex with WT EGFR
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Cancer / Drug Discovery / Drug Resistance
Function / homology
Function and homology information


multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A ...multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / intracellular vesicle / 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 / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / ossification / SHC1 events in ERBB2 signaling / basal plasma membrane / positive regulation of DNA repair / cellular response to epidermal growth factor stimulus / positive regulation of DNA replication / epithelial cell proliferation / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / EGFR downregulation / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / cell-cell adhesion / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / negative regulation of protein catabolic process / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / positive regulation of fibroblast proliferation / cell morphogenesis / neuron differentiation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / cell junction / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / Cargo recognition for clathrin-mediated endocytosis / PIP3 activates AKT signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / virus receptor activity / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of cell growth / double-stranded DNA binding / protein tyrosine kinase activity / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade
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: 2.53 Å
AuthorsDamghani, T. / Heppner, D.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM15535 United States
CitationJournal: J.Med.Chem. / Year: 2025
Title: Profiling and Optimizing Targeted Covalent Inhibitors through EGFR-Guided Studies.
Authors: Damghani, T. / Chitnis, S.P. / Abidakun, O.A. / Patel, K.B. / Lin, K.S. / Ouellette, E.A. / Lantry, A.M. / Heppner, D.E.
History
DepositionFeb 26, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 8, 2025Provider: repository / Type: Initial release

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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)37,8322
Polymers37,3041
Non-polymers5281
Water57632
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)145.390, 145.390, 145.390
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23
Space group name HallI223
Symmetry operation#1: x,y,z
#2: z,x,y
#3: y,z,x
#4: -y,-z,x
#5: z,-x,-y
#6: -y,z,-x
#7: -z,-x,y
#8: -z,x,-y
#9: y,-z,-x
#10: x,-y,-z
#11: -x,y,-z
#12: -x,-y,z
#13: x+1/2,y+1/2,z+1/2
#14: z+1/2,x+1/2,y+1/2
#15: y+1/2,z+1/2,x+1/2
#16: -y+1/2,-z+1/2,x+1/2
#17: z+1/2,-x+1/2,-y+1/2
#18: -y+1/2,z+1/2,-x+1/2
#19: -z+1/2,-x+1/2,y+1/2
#20: -z+1/2,x+1/2,-y+1/2
#21: y+1/2,-z+1/2,-x+1/2
#22: x+1/2,-y+1/2,-z+1/2
#23: -x+1/2,y+1/2,-z+1/2
#24: -x+1/2,-y+1/2,z+1/2

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Components

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


Mass: 37304.129 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 696-1022)
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-A1BYL / Almonertinib, bound form


Mass: 527.660 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C30H37N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / 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: 3.43 Å3/Da / Density % sol: 64.17 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 mM MES, 1.0 M sodium citrate, 5 mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.979338 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 6, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979338 Å / Relative weight: 1
ReflectionResolution: 2.53→102.806 Å / Num. obs: 16285 / % possible obs: 95.1 % / Redundancy: 8 % / Biso Wilson estimate: 52.56 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.197 / Rrim(I) all: 0.211 / Net I/σ(I): 7.4
Reflection shellResolution: 2.53→2.578 Å / Rmerge(I) obs: 1.891 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 861 / CC1/2: 0.39 / Rrim(I) all: 2.021

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
XDSBUILT 20241002data reduction
Aimless0.7.7data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.53→51.4 Å / SU ML: 0.4078 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.7032
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2811 868 5.34 %
Rwork0.2299 15386 -
obs0.2326 16254 94.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 61.86 Å2
Refinement stepCycle: LAST / Resolution: 2.53→51.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2135 0 39 32 2206
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00512221
X-RAY DIFFRACTIONf_angle_d0.81123007
X-RAY DIFFRACTIONf_chiral_restr0.0554339
X-RAY DIFFRACTIONf_plane_restr0.0053369
X-RAY DIFFRACTIONf_dihedral_angle_d16.5247827
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.53-2.690.36851540.29842315X-RAY DIFFRACTION86.81
2.69-2.90.34381470.262671X-RAY DIFFRACTION100
2.9-3.190.29481290.26472690X-RAY DIFFRACTION100
3.19-3.650.27341240.23862484X-RAY DIFFRACTION92.19
3.68-4.60.26441330.20082460X-RAY DIFFRACTION94.43
4.61-51.40.26551810.21932766X-RAY DIFFRACTION99.86
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.2813486615-1.57271896048-1.119733991416.15725199510.9780529212173.24416452178-0.1095533181710.186397101881-0.221624198654-0.8654858878130.007369412259450.01906705840170.1421712438540.06070341855350.08735979798110.503921511604-0.026297080390.09133107716780.3723032241560.02748545850540.3336722268037.2379468327531.486851713852.5853035788
24.295869958861.55909654913-1.208582670252.09258688113-0.6159293701120.874589676314-0.1929369007460.5134112301410.238408215728-0.440515605820.3019066555890.2613859593690.151650807728-0.173556244942-0.09706987842630.463129702456-0.0621331585611-0.004035269251770.3366292952020.04070148211270.413578767785-13.426975341322.647749686260.5875385835
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 698 through 768 )698 - 7681 - 56
22chain 'A' and (resid 769 through 1017 )769 - 101757 - 266

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