3W2Q

EGFR kinase domain T790M/L858R mutant with HKI-272


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-Based Approach for the Discovery of Pyrrolo[3,2-d]pyrimidine-Based EGFR T790M/L858R Mutant Inhibitors.

Sogabe, S.Kawakita, Y.Igaki, S.Iwata, H.Miki, H.Cary, D.R.Takagi, T.Takagi, S.Ohta, Y.Ishikawa, T.

(2013) ACS Med Chem Lett 4: 201-205

  • DOI: https://doi.org/10.1021/ml300327z
  • Primary Citation of Related Structures:  
    3W2O, 3W2P, 3W2Q, 3W2R, 3W2S

  • PubMed Abstract: 

    The epidermal growth factor receptor (EGFR) family plays a critical role in vital cellular processes and in various cancers. Known EGFR inhibitors exhibit distinct antitumor responses against the various EGFR mutants associated with nonsmall-cell lung cancer. The L858R mutation enhances clinical sensitivity to gefitinib and erlotinib as compared with wild type and reduces the relative sensitivity to lapatinib. In contrast, the T790M mutation confers drug resistance to gefitinib and erlotinib. We determined crystal structures of the wild-type and T790M/L858R double mutant EGFR kinases with reversible and irreversible pyrrolo[3,2-d]pyrimidine inhibitors based on analogues of TAK-285 and neratinib. In these structures, M790 adopts distinct conformations to accommodate different inhibitors, whereas R858 allows conformational variations of the activation loop. These results provide structural insights for understanding the structure-activity relationships that should contribute to the development of potent inhibitors against drug-sensitive or -resistant EGFR mutations.


  • Organizational Affiliation

    Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Epidermal growth factor receptor331Homo 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HKI
Query on HKI

Download Ideal Coordinates CCD File 
B [auth A]N-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)butanamide
C30 H31 Cl N6 O3
MIURWHKJMYMLCP-UHFFFAOYSA-N
MES
Query on MES

Download Ideal Coordinates CCD File 
C [auth A]2-(N-MORPHOLINO)-ETHANESULFONIC ACID
C6 H13 N O4 S
SXGZJKUKBWWHRA-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
HKI PDBBind:  3W2Q IC50: 66 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 
  • Space Group: I 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 144.113α = 90
b = 144.113β = 90
c = 144.113γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-01-16
    Type: Initial release
  • Version 1.1: 2013-08-21
    Changes: Database references
  • Version 1.2: 2019-12-25
    Changes: Database references, Derived calculations
  • Version 1.3: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description