Structural basis for the recognition of Sonic Hedgehog by human Patched1

The first step in Hedgehog signaling The Hedgehog (Hh) signaling pathway is important in embryogenesis; overactivation is associated with cancer. Central to the pathway is the membrane receptor Patched 1 (Ptch1), which indirectly inhibits a G protein–coupled receptor called Smoothened. This inhibition is relieved when Ptch1 binds the secreted protein Hh. Gong et al. report the cryo–electron microscopy structures of human Ptch1 alone and in complex with its Hh ligand at 3.9 and 3.6 Å, respectively. Both structures include two steroid-shaped densities, and mutational analysis indicates that the interaction between Ptch1 and Hh is steroid-dependent. Science , this issue p. eaas8935