4HRN
Structural Basis for Eliciting a Cytotoxic Effect in HER2-Overexpressing Cancer Cells via Binding to the Extracellular Domain of HER2
Summary for 4HRN
| Entry DOI | 10.2210/pdb4hrn/pdb |
| Related | 1N8Z 1S78 2JAB 3H3B 4HRL 4HRM |
| Descriptor | Designed Ankyrin Repeat Protein H10-2-G, Receptor tyrosine-protein kinase erbB-2 (2 entities in total) |
| Functional Keywords | transferase-de novo protein complex, transferase/de novo protein |
| Biological source | synthetic More |
| Cellular location | Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Cytoplasm. Isoform 3: Cytoplasm: P04626 |
| Total number of polymer chains | 4 |
| Total formula weight | 52553.25 |
| Authors | Jost, C.,Schilling, J.,Plueckthun, A. (deposition date: 2012-10-28, release date: 2013-10-16, Last modification date: 2023-11-08) |
| Primary citation | Jost, C.,Schilling, J.,Tamaskovic, R.,Schwill, M.,Honegger, A.,Plueckthun, A. Structural Basis for Eliciting a Cytotoxic Effect in HER2-Overexpressing Cancer Cells via Binding to the Extracellular Domain of HER2. Structure, 21:1-13, 2013 Cited by PubMed Abstract: 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. PubMed: 24095059DOI: 10.1016/j.str.2013.08.020 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
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