4HRN

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

4HRN の概要

• エントリーDOI: 10.2210/pdb4hrn/pdb
• 関連するPDBエントリー: 1N8Z 1S78 2JAB 3H3B 4HRL 4HRM
• 分子名称: Designed Ankyrin Repeat Protein H10-2-G, Receptor tyrosine-protein kinase erbB-2 (2 entities in total)
• 機能のキーワード: transferase-de novo protein complex, transferase/de novo protein
• 由来する生物種: synthetic; 詳細
• 細胞内の位置: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Cytoplasm. Isoform 3: Cytoplasm: P04626
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 52553.25

構造登録者

Jost, C.,Schilling, J.,Plueckthun, A. (登録日: 2012-10-28, 公開日: 2013-10-16, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.65 Å)