PDBsum entry 4zau

Transferase/transferase inhibitor

PDB id: 4zau

Contents

Protein chain

283 a.a.

Ligands

YY3

Waters ×4

PDB id:

4zau

Name:

Transferase/transferase inhibitor

Title:

Azd9291 complex with wild type egfr

Structure:

Epidermal growth factor receptor. Chain: a. Fragment: unp residues 696-1022. Synonym: proto-oncogenE C-erbb-1,receptor tyrosine-protein kinase erbb-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.80Å R-factor: 0.196 R-free: 0.244

Authors:

C.J.Squire,Y.Yosaatmadja,J.U.Flanagan,M.Mckeage

Key ref:

Y.Yosaatmadja et al. (2015). Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed. J Struct Biol, 192, 539-544. PubMed id: 26522274 DOI: 10.1016/j.jsb.2015.10.018

Date:

14-Apr-15 Release date: 11-Nov-15

Protein chain

P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor from Homo sapiens

Seq: 1210 a.a.

Struc: 283 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.jsb.2015.10.018

J Struct Biol 192:539-544 (2015)

PubMed id: 26522274

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

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

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.