Structure and Mechanism-Based Design of ErbB Receptor Inhibitors
Abstract
The HER4/ErbB4 receptor tyrosine kinase is inhibited by lapatinib (Tykerb"), and a crystal structure of the HER4/ErbB4 kinase domain complexed with lapatinib reveals an inactive conformation of the kinase and the specific molecular contacts made between HER4/ErbB4 and lapatinib. A crystal structure of the HER4/ErbB4 kinase domain in an active conformation reveals an asymmetric dimer contact virtually identical to an interaction observed for the related epidermal growth factor receptor. Mutagenesis studies demonstrate this dimer contact to be essential for normal kinase activation and show this activation mechanism to be a general feature of the ErbB family of receptor tyrosine kinases. An integral membrane form of the epidermal growth factor receptor has been expressed and purified and will form the basis for future structural and functional studies of the EGFR/ErbB family of receptors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2007
- Accession Number
- ADA475507
Entities
People
- Daniel J. Leahy
Organizations
- Johns Hopkins University