Klein Lab at Yale • Mechanistic Viewer
Mechanism of ROS1 activation and inhibition
Inactive
Monomer
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Unliganded ROS1
A bent ectodomain tucks the small CATCH hand into a pocket around the YWTD-B hip domain. The arm and hand move as one rigid unit, the leg stays constrained, and ROS1 remains inactive.
What the model encodes
The domain structure of ROS1 from N-terminus to C-terminus: CATCH, FNIII-1, FNIII-2, YWTD-A, FNIII-3, YWTD-B, FNIII-4, FNIII-5, YWTD-C, FNIII-6, FNIII-7, FNIII-8, FNIII-9, and then the transmembrane helix.
Structural anchors
This is a mechanistic cartoon, not an atom-by-atom simulation. It is grounded in the structures reported in our ROS1 paper and the linked PDB entries: 9PVP, 10FT, 10GH, 9DZ4, and 9PWQ.
Mechanistic logic
In the inactive and site-1 clustered states, the CATCH hand stays parked in the YWTD-B hip pocket. In the active state, NELL2 remains anchored at site 1 on YWTD-A while the arm flips upward as a rigid CATCH plus FNIII-1/2 body, adding site 2 on FNIII-2 and site 3 on FNIII-1. The NELL2 trimer itself stays rigid, with the same fixed conformation whether it is bound or unbound off to the side. CATCH does not bind NELL2; it simply releases from YWTD-B so the legs can come closer together and the kinase regions can engage.
Antibody blockade
RX5 is drawn as a Y-shaped antibody whose one Fab tip caps the site-1 epitope on YWTD-A and prevents productive NELL2 recruitment. CT4 is drawn as the same Y-shaped antibody, but with one Fab tip docked into the arm-shoulder interface so the arm cannot flip up to add site 2 on FNIII-2 and site 3 on FNIII-1, trapping a pre-active clustered state.