8H7X

Crystal structure of EGFR T790M/C797S mutant in complex with brigatinib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.40 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.189 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

A macrocyclic kinase inhibitor overcomes triple resistant mutations in EGFR-positive lung cancer.

Suzuki, M.Uchibori, K.Oh-Hara, T.Nomura, Y.Suzuki, R.Takemoto, A.Araki, M.Matsumoto, S.Sagae, Y.Kukimoto-Niino, M.Kawase, Y.Shirouzu, M.Okuno, Y.Nishio, M.Fujita, N.Katayama, R.

(2024) NPJ Precis Oncol 8: 46-46

  • DOI: https://doi.org/10.1038/s41698-024-00542-9
  • Primary Citation of Related Structures:  
    8H7X

  • PubMed Abstract: 

    Brigatinib-based therapy was effective against osimertinib-resistant EGFR C797S mutants and is undergoing clinical studies. However, tumor relapse suggests additional resistance mutations might emerge. Here, we first demonstrated the binding mode of brigatinib to the EGFR-T790M/C797S mutant by crystal structure analysis and predicted brigatinib-resistant mutations through a cell-based assay including N-ethyl-N-nitrosourea (ENU) mutagenesis. We found that clinically reported L718 and G796 compound mutations appeared, consistent with their proximity to the binding site of brigatinib, and brigatinib-resistant quadruple mutants such as EGFR-activating mutation/T790M/C797S/L718M were resistant to all the clinically available EGFR-TKIs. BI-4020, a fourth-generation EGFR inhibitor with a macrocyclic structure, overcomes the quadruple and major EGFR-activating mutants but not the minor mutants, such as L747P or S768I. Molecular dynamics simulation revealed the binding mode and affinity between BI-4020 and EGFR mutants. This study identified potential therapeutic strategies using the new-generation macrocyclic EGFR inhibitor to overcome the emerging ultimate resistance mutants.


  • Organizational Affiliation

    Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Epidermal growth factor receptor
A, B
330Homo sapiensMutation(s): 2 
Gene Names: EGFRERBBERBB1HER1
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00533 (Homo sapiens)
Explore P00533 
Go to UniProtKB:  P00533
PHAROS:  P00533
GTEx:  ENSG00000146648 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00533
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6GY (Subject of Investigation/LOI)
Query on 6GY

Download Ideal Coordinates CCD File 
C [auth A]5-chloro-N~4~-[2-(dimethylphosphoryl)phenyl]-N~2~-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine
C29 H39 Cl N7 O2 P
AILRADAXUVEEIR-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6GY BindingDB:  8H7X IC50: min: 0.7, max: 1700 (nM) from 37 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.40 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.189 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.1α = 90
b = 90.11β = 90
c = 165.31γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
XDSdata scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Japan Agency for Medical Research and Development (AMED)Japan--

Revision History  (Full details and data files)

  • Version 1.0: 2023-10-25
    Type: Initial release
  • Version 1.1: 2024-03-06
    Changes: Database references