Colocalization Strategy Unveils an Underside Binding Site in the Transmembrane Domain of Smoothened Receptor

We unveiled an underside
binding site on smoothened receptor (SMO)
by a colocalization strategy using two structurally complementary
photoaffinity probes derived from a known ligand Allo-1. Docking study
and structural dissection identified key interactions within the site,
including hydrogen bonding, π–π interactions, and
hydrophobic interactions between Allo-1 and its contacting residues.
Taken together, our results reveal the molecular base of Allo-1 binding
and provide a basis for the design of new-generation ligands to overcome
drug resistance.