Smoothened receptor (SMO) (SMO)

Smoothened receptor (SMO) is a Class Frizzled (Class F) G protein-coupled receptor that functions as a key signal transducer in the Hedgehog signaling pathway, conserved from flies to humans. SMO contains an extracellular cysteine-rich domain (CRD), a seven-transmembrane domain (7TM), and an intracellular tail; ligands bind both the 7TM core (cyclopamine/vismodegib site) and the CRD (oxysterols) to allosterically regulate activation. Structural studies reveal a multi-domain architecture enabling allosteric interactions between the CRD, hinge domain, and 7TM core that underlie distinctive activation mechanisms among GPCRs. SMO activity is normally inhibited by the Hedgehog receptor Patched (PTCH); loss of PTCH or activating SMO mutations drives aberrant pathway signaling implicated in cancers such as basal cell carcinoma. Clinically, SMO is a validated therapeutic target; vismodegib is an FDA-approved antagonist, while other tool molecules include antagonists like SANT-1 and natural inhibitor cyclopamine and the agonist SAG.

Other names

SmoothenedSmoothened homologueSmoProtein smoothenedClass F GPCR Smoothened

Small-molecule antagonists that bind the SMO 7-transmembrane (7TM) core/cyclopamine site to inhibit Hh signaling (e.g., vismodegib, cyclopamine, SANT-1). Small-molecule agonists that bind the 7TM site to activate SMO (e.g., SAG). Modulation via sterol/oxysterol binding to the extracellular cysteine-rich domain (CRD) to regulate activation.