Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm

Nat Commun. 2019 May 24;10(1):2320. doi: 10.1038/s41467-019-10234-9.


The Hedgehog (Hh) pathway controls embryonic development and postnatal tissue maintenance and regeneration. Inhibition of Hh receptor Patched (Ptch) by the Hh ligands relieves suppression of signaling cascades. Here, we report the cryo-EM structure of tetrameric Ptch1 in complex with the palmitoylated N-terminal signaling domain of human Sonic hedgehog (ShhNp) at a 4:2 stoichiometric ratio. The structure shows that four Ptch1 protomers are organized as a loose dimer of dimers. Each dimer binds to one ShhNp through two distinct inhibitory interfaces, one mainly through the N-terminal peptide and the palmitoyl moiety of ShhNp and the other through the Ca2+-mediated interface on ShhNp. Map comparison reveals that the cholesteryl moiety of native ShhN occupies a recently identified extracellular steroid binding pocket in Ptch1. Our structure elucidates the tetrameric assembly of Ptch1 and suggests an asymmetric mode of action of the Hh ligands for inhibiting the potential cholesterol transport activity of Ptch1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cholesterol / metabolism
  • Cryoelectron Microscopy
  • HEK293 Cells
  • Hedgehog Proteins / chemistry
  • Hedgehog Proteins / isolation & purification
  • Hedgehog Proteins / metabolism
  • Hedgehog Proteins / ultrastructure*
  • Humans
  • Ligands
  • Lipoylation
  • Models, Molecular
  • Patched-1 Receptor / isolation & purification
  • Patched-1 Receptor / metabolism
  • Patched-1 Receptor / ultrastructure*
  • Protein Binding
  • Protein Domains*
  • Protein Multimerization
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / ultrastructure


  • Hedgehog Proteins
  • Ligands
  • PTCH1 protein, human
  • Patched-1 Receptor
  • Recombinant Proteins
  • SHH protein, human
  • Cholesterol