Crystal Structure Clarifies Antibody Binding to HER2

A recent study describes the crystal structures of the entire extracellular regions of rat epidermal growth factor HER2 and human HER2 complexed with the Herceptin antigen-binding fragment (Fab). The study appeared in the February 13, 2003, issue of Nature.

HER2 (ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20–30% of human breast cancers, and correlates with more aggressive tumors and a poorer prognosis. Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin, is currently in use as a treatment for breast cancer.

Investigators from Johns Hopkins University (Baltimore, MD, USA; www.jhu.edu) and Genitope Corporation (Redwood City, CA, USA; www.genitope.com) grew crystals of the extracellular region of the HER2 protein. Data obtained after bombarding the crystals with radiation was interpreted to create the protein's structure. The same approach was taken with crystals of HER2 bound to the Fab fragment of the Herceptin antibody.

The extracellular regions of all the HER proteins are made up of four structurally distinct ‘domains', I, II, III and IV. In HER1 and 3, a fingerlike projection in domain II keeps it connected to domain IV, forming a bracelet-like loop. In HER2, however, a tight interaction between domains I and III prevents the bracelet formation. Therefore, domain IV is available for binding to Herceptin, and domain II for pairing with other HER proteins.

"Now we know exactly which building blocks of the Herceptin antibody interact with which building blocks of HER2,” explained senior author Dr. Dan Leahy, professor of biophysics at the Johns Hopkins School of Medicine. "When you understand the properties of receptors and antibodies in terms of their structural interaction, you can begin to explain their effects and use the information to design better drugs.”




Related Links:
Johns Hopkins University
Genitope Corporation