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Structural basis for the recognition of Sonic Hedgehog by human Patched1
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Structural basis for the recognition of Sonic Hedgehog by human Patched1
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Structural basis for the recognition of Sonic Hedgehog by human Patched1
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Journal Article
Structural basis for the recognition of Sonic Hedgehog by human Patched1
2018
Overview
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 The cryo–electron microscopy structure of the human receptor for the regulator of development and regeneration shows steroid dependency. The Hedgehog (Hh) pathway involved in development and regeneration is activated by the extracellular binding of Hh to the membrane receptor Patched (Ptch). We report the structures of human Ptch1 alone and in complex with the N-terminal domain of human Sonic hedgehog (ShhN) at resolutions of 3.9 and 3.6 angstroms, respectively, as determined by cryo–electron microscopy. Ptch1 comprises two interacting extracellular domains, ECD1 and ECD2, and 12 transmembrane segments (TMs), with TMs 2 to 6 constituting the sterol-sensing domain (SSD). Two steroid-shaped densities are resolved in both structures, one enclosed by ECD1/2 and the other in the membrane-facing cavity of the SSD. Structure-guided mutational analysis shows that interaction between ShhN and Ptch1 is steroid-dependent. The structure of a steroid binding–deficient Ptch1 mutant displays pronounced conformational rearrangements.
