8VQD

HER2 S310F in complex with TL1 Fab

8VQD の概要

• エントリーDOI: 10.2210/pdb8vqd/pdb
• 関連するPDBエントリー: 8VQE
• EMDBエントリー: 43439 43440
• 分子名称: Receptor tyrosine-protein kinase erbB-2/hIgG1 Fc domain fusion, Variable Heavy chain of TL1 Fab, Variable Light chain of TL1 Fab, ... (4 entities in total)
• 機能のキーワード: her2, fab, tyrosine kinase receptor, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 150538.52

構造登録者

Bang, I.,Koide, S. (登録日: 2024-01-18, 公開日: 2024-10-09, 最終更新日: 2025-05-14)

主引用文献

Bang, I.,Hattori, T.,Leloup, N.,Corrado, A.,Nyamaa, A.,Koide, A.,Geles, K.,Buck, E.,Koide, S.
Selective targeting of oncogenic hotspot mutations of the HER2 extracellular domain.
Nat.Chem.Biol., 21:706-715, 2025

PubMed Abstract: Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been identified in receptor tyrosine kinases including HER2. However, it is challenging to selectively target a point mutant, while sparing the wild-type protein. Here we developed antibodies selective to HER2 S310F and S310Y, the two most common oncogenic mutations in the HER2 ECD, via combinatorial library screening and structure-guided design. Cryogenic-electron microscopy structures of the HER2 S310F homodimer and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimics the dimerization arm of HER2 and thus inhibit HER2 dimerization. These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development.

PubMed: 39438724
DOI: 10.1038/s41589-024-01751-w

実験手法

ELECTRON MICROSCOPY (2.61 Å)