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TitleClustering and a conformational switch drive activation of the mammalian receptor tyrosine kinase ROS1.
Journal, issue, pagesNat Commun, Year 2026
Publish dateFeb 17, 2026
AuthorsHengyi Li / Jianan Zhang / Tongqing Li / Yueyue Wang / Claudio R Alarcón / Daryl E Klein /
PubMed AbstractReceptor 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 ...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.
External linksNat Commun / PubMed:41698918
MethodsEM (single particle)
Resolution2.99 - 4.57 Å
Structure data

47324

9dz4

EMDB-47324, PDB-9dz4:
Cryo-EM Structure of Receptor Tyrosine Kinase ROS1 in Complex with Fab-CT4
Method: EM (single particle) / Resolution: 2.99 Å

71895

9pvp

EMDB-71895, PDB-9pvp:
Cryo-EM structure of receptor tyrosine kinase ROS1 extracellular domain
Method: EM (single particle) / Resolution: 4.57 Å

71938

9pwq

EMDB-71938, PDB-9pwq:
Cryo-EM structure of receptor tyrosine kinase ROS1 extracellular domain in complex with NELL2
Method: EM (single particle) / Resolution: 4.45 Å

75142

10ft

EMDB-75142, PDB-10ft:
Cryo-EM structure of receptor tyrosine kinase ROS1 in complex with NELL2
Method: EM (single particle) / Resolution: 3.21 Å

75151

10gh

EMDB-75151, PDB-10gh:
Cryo-EM structure of Receptor Tyrosine Kinase ROS1 in complex with Fab-RX5
Method: EM (single particle) / Resolution: 3.06 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsTRANSFERASE / Receptor tyrosine kinase ROS1 / ROS1-NELL2 complex / TRANSFERASE-SIGNALING PROTEIN complex / TRANSFERASE/IMMUNE SYSTEM / Receptor tyrosine kinase / ROS1 extracellular bent-over conformation / Inhibitory Fab-RX5 / TRANSFERASE-IMMUNE SYSTEM complex / Inhibitory Fab-CT4 / TRANSFERASE/SIGNALING PROTEIN

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