PDBsum entry 3w2o

Transferase/transferase inhibitor

PDB id: 3w2o

Contents

Protein chain

305 a.a.

Ligands

03P

Waters ×37

PDB id:

3w2o

Name:

Transferase/transferase inhibitor

Title:

Egfr kinase domain t790m/l858r mutant with tak-285

Structure:

Epidermal growth factor receptor. Chain: a. Fragment: kinase domain, unp residues 698-1022. Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein kinase erbb-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.35Å R-factor: 0.182 R-free: 0.216

Authors:

S.Sogabe,Y.Kawakita,S.Igaki

Key ref:

S.Sogabe et al. (2013). Structure-Based Approach for the Discovery of Pyrrolo[3,2-d]pyrimidine-Based EGFR T790M/L858R Mutant Inhibitors. ACS Med Chem Lett, 4, 201-205. PubMed id: 24900643 DOI: 10.1021/ml300327z

Date:

03-Dec-12 Release date: 16-Jan-13

Protein chain

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

Seq: 1210 a.a.

Struc: 305 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

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: 10.1021/ml300327z

ACS Med Chem Lett 4:201-205 (2013)

PubMed id: 24900643

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

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

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.