9OZC

Cryo-EM structure of 1:2:1 ROS1/NEL/NICOL holo-complex, conformation 1.

This is a non-PDB format compatible entry.

Summary for 9OZC

• Entry DOI: 10.2210/pdb9ozc/pdb
• EMDB information: 71057
• Descriptor: Tyrosine-protein kinase receptor, Protein NEL, NELL2-interacting cell ontogeny regulator 1, ... (6 entities in total)
• Functional Keywords: ros1, nel, signaling protein
• Biological source: Gallus gallus (chicken); More
• Total number of polymer chains: 4
• Total formula weight: 461552.30

Authors

An, W.D.,Zhang, X.W.,Bai, X.C. (deposition date: 2025-06-05, release date: 2026-02-25, Last modification date: 2026-04-08)

Primary citation

An, W.,Zhang, X.,Bai, X.C.
Structural insights into the activation of the chicken ROS1 receptor by the NEL/NICOL ligand complex.
Nat Commun, 17:-, 2026

PubMed Abstract: The receptor tyrosine kinase ROS1 plays essential roles in cell growth and sperm maturation, yet its activation mechanism has remained poorly understood. Here, we report high-resolution cryo-electron microscopy (cryo-EM) structures of chicken ROS1 in its ligand-free form, in complex with its ligand NEL, and with the ligand/co-ligand complex NEL/NICOL. Unliganded ROS1 adopts an arc-shaped conformation. The interaction between NEL and ROS1 is mediated by the VWC2 domain of NEL and the β1 domain of ROS1. Binding of NICOL to the coiled-coil domain of NEL stabilizes NEL into a batwing-shaped asymmetric dimer, which can recruit only one ROS1 molecule due to steric hindrance. Structural analyses and biochemical results suggest that the 2:1 NEL/NICOL complexes further oligomerize through LamG-VWC4 domain interactions, facilitating the clustering of multiple ROS1 for its activation. Functional assays confirm that both NICOL and the multimerization of NEL/NICOL complexes are required for robust ROS1 signaling. Our findings establish NICOL as a critical co-ligand for ROS1 and suggest a distinct ligand-driven oligomerization mechanism for ROS1 activation.

PubMed: 41735298
DOI: 10.1038/s41467-026-69942-8

Experimental method

ELECTRON MICROSCOPY (4 Å)