Journal
STRUCTURE
Volume 21, Issue 11, Pages 1979-1991Publisher
CELL PRESS
DOI: 10.1016/j.str.2013.08.020
Keywords
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Funding
- Swiss National Center of Competence in Research in Structural Biology, Schweizerischer National-fonds grant [3100A0-113720]
- Krebsforschung Schweiz grant [KFS-02448-08-2009]
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Human epidermal growth factor receptor-2 (HER2) is a receptor tyrosine kinase directly linked to the growth of malignancies from various origins and a validated target for monoclonal antibodies and kinase inhibitors. Utilizing a new approach with designed ankyrin repeat proteins (DARPins) as alternative binders, we show that binding of two DARPins connected by a short linker, one targeting extracellular subdomain I and the other subdomain IV, causes much stronger cytotoxic effects on the HER2-addicted breast cancer cell line BT474, surpassing the therapeutic antibody trastuzumab. We determined crystal structures of these DARPins in complex with the respective subdomains. Detailed models of the full-length receptor, constrained by its rigid domain structures and its membrane anchoring, explain how the bispecific DARPins connect two membrane-bound HER2 molecules, distorting them such that they cannot form signaling-competent dimers with any EGFR family member, preventing any kinase dimerization, and thus leading to a complete loss of signaling.
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