10FT

Cryo-EM structure of receptor tyrosine kinase ROS1 in complex with NELL2

10FT の概要

• エントリーDOI: 10.2210/pdb10ft/pdb
• EMDBエントリー: 75142
• 分子名称: Protein kinase C-binding protein NELL2, Proto-oncogene tyrosine-protein kinase ROS, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• 機能のキーワード: receptor tyrosine kinase ros1, ros1-nell2 complex, transferase-signaling protein complex, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 205579.45

構造登録者

Li, H.,Klein, D. (登録日: 2026-01-17, 公開日: 2026-02-25, 最終更新日: 2026-05-06)

主引用文献

Li, H.,Zhang, J.,Li, T.,Wang, Y.,Alarcon, C.R.,Klein, D.E.
Clustering and a conformational switch drive activation of the mammalian receptor tyrosine kinase ROS1.
Nat Commun, 17:-, 2026

PubMed Abstract: Receptor tyrosine kinases (RTKs) are key regulators of cellular signaling and are often co-opted in cancer. ROS1 is an orphan RTK aberrantly expressed in multiple tumors, yet no approved biologic therapies target it, and its activation mechanism remains unknown. Here, we present Cryo-EM structures of mammalian ROS1 in ligand-free and NELL2-bound states, revealing how trimeric NELL2 induces both receptor clustering and a conformational switch that relieves receptor autoinhibition - both mechanisms are required for ROS1 activation. These structures, along with biochemical characterization, reflect a striking evolutionary divergence in regulatory logic compared to the invertebrate ortholog Sevenless (dROS1), highlighting how conserved RTKs can adopt fundamentally different activation strategies. Guided by these structural insights, we develop monoclonal antibodies that either block ligand binding or trap ROS1 in an inactive conformation. These agents potently suppress ROS1 signaling, representing distinct mechanistic classes of biologics that directly target ROS1 activity. Our findings elucidate a distinct mode of RTK regulation and establish a therapeutic framework for cancers driven by ROS1.

PubMed: 41698918
DOI: 10.1038/s41467-026-69630-7

実験手法

ELECTRON MICROSCOPY (3.21 Å)