4HRL

Structural Basis for Eliciting a Cytotoxic Effect in HER2-Overexpressing Cancer Cells via Binding to the Extracellular Domain of HER2

Summary for 4HRL

• Entry DOI: 10.2210/pdb4hrl/pdb
• Related: 1N8Z 1S78 3H3B 3MZW 4HRM 4HRN
• Descriptor: Receptor tyrosine-protein kinase erbB-2, Designed Ankyrin Repeat Protein 9_29 (3 entities in total)
• Functional Keywords: transferase-de novo protein complex, transferase/de novo protein
• Biological source: Homo sapiens (human); 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: 2
• Total formula weight: 40766.96

Authors

Jost, C.,Schilling, J.,Plueckthun, A. (deposition date: 2012-10-28, release date: 2013-10-16, Last modification date: 2024-10-16)

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

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: 24095059
DOI: 10.1016/j.str.2013.08.020

Experimental method

X-RAY DIFFRACTION (2.55 Å)