8H7X | pdb_00008h7x

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 (Depositor), 0.260 (DCC) 
  • R-Value Work: 
    0.181 (Depositor), 0.180 (DCC) 
  • R-Value Observed: 
    0.189 (Depositor) 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 6GYClick on this verticalbar to view details

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: 1718 (nM) from 47 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.40 Å
  • R-Value Free:  0.256 (Depositor), 0.260 (DCC) 
  • R-Value Work:  0.181 (Depositor), 0.180 (DCC) 
  • R-Value Observed: 0.189 (Depositor) 
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 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 6GYClick on this verticalbar to view details

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