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- PDB-9mss: Limertinib in complex with WT EGFR -

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Basic information

Entry
Database: PDB / ID: 9mss
TitleLimertinib in complex with WT EGFR
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Cancer / Kinase / Drug Discovery
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 / positive regulation of DNA repair / basal plasma membrane / 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 / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / cell morphogenesis / positive regulation of fibroblast proliferation / 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 / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / 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: 2.09 Å
AuthorsDamghani, T. / Lin, K.S. / Heppner, D.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM155353 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
DepositionJan 10, 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)37,8522
Polymers37,3041
Non-polymers5481
Water1,820101
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 area14460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.186, 146.186, 146.186
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
Components on special symmetry positions
IDModelComponents
11A-1298-

HOH

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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-A1BYO / Limertinib. bound form


Mass: 548.079 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H34ClN7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 101 / 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: 3.49 Å3/Da / Density % sol: 64.75 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 1.0 M sodium citrate, 0.1 MES, 5.0 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: 0.920105 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 5, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.920105 Å / Relative weight: 1
ReflectionResolution: 2.086→34.46 Å / Num. obs: 31022 / % possible obs: 100 % / Redundancy: 6.9 % / Biso Wilson estimate: 48.12 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.084 / Rpim(I) all: 0.034 / Rrim(I) all: 0.091 / Net I/σ(I): 11.7
Reflection shellResolution: 2.086→2.122 Å / Redundancy: 7.2 % / Rmerge(I) obs: 2.478 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 11162 / CC1/2: 0.335 / Rpim(I) all: 0.995 / Rrim(I) all: 2.676 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
XDSBUILT 20230630data reduction
Aimless0.7.7data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.09→34.46 Å / SU ML: 0.3008 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.702
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2375 1555 5.03 %
Rwork0.2212 29376 -
obs0.222 30931 99.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 55.3 Å2
Refinement stepCycle: LAST / Resolution: 2.09→34.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2282 0 39 101 2422
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00542370
X-RAY DIFFRACTIONf_angle_d0.7363209
X-RAY DIFFRACTIONf_chiral_restr0.0519359
X-RAY DIFFRACTIONf_plane_restr0.0072399
X-RAY DIFFRACTIONf_dihedral_angle_d16.4852879
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.09-2.150.36391400.33262637X-RAY DIFFRACTION98.76
2.15-2.230.34321500.29162627X-RAY DIFFRACTION100
2.23-2.320.29451320.28142671X-RAY DIFFRACTION99.93
2.32-2.430.26821280.2652660X-RAY DIFFRACTION100
2.43-2.550.33711540.25882643X-RAY DIFFRACTION99.96
2.55-2.710.27321220.25452649X-RAY DIFFRACTION98.79
2.71-2.920.30461460.2472664X-RAY DIFFRACTION99.93
2.92-3.220.25621470.2462680X-RAY DIFFRACTION100
3.22-3.680.24731280.21882673X-RAY DIFFRACTION99.79
3.68-4.630.20111440.18442701X-RAY DIFFRACTION100
4.64-34.460.19711640.1992771X-RAY DIFFRACTION99.9

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