STRUCTURES OF THE EXTRACELLULAR DOMAIN OF THE EPIDERMAL GROWTH FACTOR

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Using data collected at CHESS A1, we recently solved the structure of the extracellular domain of the epidermal growth factor receptor (sEGFR) in complex with the antigen binding fragment (Fab) of the FDA-approved anticancer drug cetuximab/Erbitux. Cetuximab is one of a group of anti-EGFR antibodies that are under intense clinical investigation, and was the first to gain FDA-approval. Each of this group of antibodies is known to block ligand dependent activation of EGFR. Our structure shows that, at least for cetuximab, the inhibitory effects are due to direct competition of the antibody for the ligand binding site on the receptor. We are interested to establish if other antibodies inhibit EGFR in the same way, or if there are other modes of binding that could also block receptor activation ¿¿¿ such as inhibition of the formation of receptor dimers. The molecular details that we can learn by studying the interactions of different antibodies with EGFR will yield valuable information to fuel the design of new and improved drugs.