4ZAU

AZD9291 complex with wild type EGFR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed.

Yosaatmadja, Y.Silva, S.Dickson, J.M.Patterson, A.V.Smaill, J.B.Flanagan, J.U.McKeage, M.J.Squire, C.J.

(2015) J Struct Biol 192: 539-544

  • DOI: https://doi.org/10.1016/j.jsb.2015.10.018
  • Primary Citation of Related Structures:  
    4ZAU

  • PubMed Abstract: 

    The discovery of genetic drivers of lung cancer in patient sub-groups has led to their use as predictive biomarkers and as targets for selective drug therapy. Some of the most important lung cancer drivers are mutations in the EGFR gene, for example, the exon 19 deletions and the L858R variant that confer sensitivity to the front line drugs erlotinib and gefitinib; the acquired T790M variants confer drug resistance and a poor prognosis. A challenge then in targeting EGFR is to produce drugs that inhibit both sensitising variants and resistance variants, leaving wild type protein in healthy cells unaffected. One such agent is AstraZeneca's "breakthrough" AZD9291 molecule that shows a 200-fold selectivity for T790M/L858R over wild type EGFR. Our X-ray crystal structure reveals the binding mode of AZD9291 to the kinase domain of wild type EGFR.


  • Organizational Affiliation

    School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Epidermal growth factor receptor330Homo sapiensMutation(s): 0 
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
YY3
Query on YY3

Download Ideal Coordinates CCD File 
B [auth A]N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide
C28 H33 N7 O2
DUYJMQONPNNFPI-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
YY3 BindingDB:  4ZAU Ki: min: 2.2, max: 14 (nM) from 4 assay(s)
IC50: min: 2.00e-3, max: 17 (nM) from 39 assay(s)
EC50: min: 6, max: 7930 (nM) from 11 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 
  • Space Group: I 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 144.886α = 90
b = 144.886β = 90
c = 144.886γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-11-11
    Type: Initial release
  • Version 1.1: 2015-11-18
    Changes: Database references
  • Version 1.2: 2015-12-02
    Changes: Database references
  • Version 1.3: 2020-09-09
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Refinement description, Structure summary