Klein Lab at Yale • Mechanistic Viewer
Mechanism of ALK activation and inhibition
Inactive
Separated monomers
Drag to rotate. Scroll to zoom. Hover for domain labels.
Unliganded ALK
Before ligand binding, ALK is shown as separated monomers whose handle-pole-PXL GRD is not yet organized into the membrane-parallel signaling arrangement. The membrane pocket that later accepts ALKAL is not productively formed, the EGF-like domain has not yet repositioned, and no symmetric dimer interface is created.
What the model encodes
The ALK ectodomain from membrane-distal to membrane-proximal: the GRD resolved as handle, pole, and PXL, followed by the EGF-like domain, transmembrane helix, and intracellular kinase domain.
Structural anchors
This is a mechanistic cartoon, not an atom-by-atom simulation. It is grounded in the structures reported in our Nature paper. Linked PDB entries: 7LS0 (human ALK GRD-ALKAL fusion complex), 7LRZ (human ALK GRD), 7LIR (worm ALK GRD), and 7MK7 (ALKAL2-AD).
Mechanistic logic
Two ligand-bound ALK receptor complexes initially lie roughly parallel to the plane of the membrane. These complexes can then associate to form an antiparallel receptor dimer. The ligand ALKAL helps stabilize this assembly by bridging a “handle” region on one receptor protomer to the PXL (poly-glycine extension loop) of the opposing protomer, effectively stitching the two complexes together and promoting formation of the active dimer.
Antibody blockade
CDX123 is drawn as a PXL-binding blocker that still permits ALKAL engagement at the handle but prevents the dimerization step. FAB125 is drawn as the monovalent handle-binding Fab: it excludes ALKAL but cannot cross-link receptors, so it stays blocking rather than activating. CDX125 is the full handle-binding agonist antibody whose two Fab tips bind two handles at once, cross-link the receptors, exclude ALKAL, and activate ALK.