Smoothened receptor D473H mutant (SMO D473H)

The Smoothened receptor D473H mutant is a specific variant of the Smoothened (SMO) protein, which is a Class F G protein-coupled receptor (GPCR) essential for the Hedgehog (Hh) signaling pathway (UniProt P57699). This mutation, characterized by the substitution of aspartic acid with histidine at residue 473 in the sixth transmembrane helix, was first identified as a primary cause of clinical resistance to the SMO inhibitor vismodegib in patients with medulloblastoma (Yauch et al., 2009). The D473 residue is critical for the binding of several small-molecule antagonists; its mutation to histidine creates steric hindrance and alters the hydrogen-bonding network within the drug-binding pocket, preventing effective inhibition by first-generation drugs like vismodegib and sonidegib (Pricl et al., 2015). This mutant is frequently encountered in cases of relapsed basal cell carcinoma and medulloblastoma, where it allows for the reactivation of the Hh pathway and subsequent tumor progression. As a result, the D473H mutant is a key target for the development of next-generation SMO antagonists, such as taladegib, which are designed to bind effectively even in the presence of this mutation (ClinicalTrials.gov).

Other names

SMO D473HSmoothened homolog D473HSMO Asp473HisSmoothened D473H

Antagonism of the Smoothened receptor to inhibit downstream Hedgehog signaling; however, this specific mutant exhibits resistance to first-generation antagonists due to binding site alterations.