6N7K

Cryo-EM structure of tetrameric Ptch1 in complex with ShhNp (form II)

Summary for 6N7K

• Entry DOI: 10.2210/pdb6n7k/pdb
• EMDB information: 0358
• Descriptor: Protein patched homolog 1, Sonic hedgehog protein, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: receptor, rnd family, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 650738.67

Authors

Yan, N.,Gong, X.,Qian, H.W. (deposition date: 2018-11-27, release date: 2019-05-29, Last modification date: 2025-05-28)

Primary citation

Qian, H.,Cao, P.,Hu, M.,Gao, S.,Yan, N.,Gong, X.
Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm.
Nat Commun, 10:2320-2320, 2019

PubMed Abstract: 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 (ShhN) 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 ShhN through two distinct inhibitory interfaces, one mainly through the N-terminal peptide and the palmitoyl moiety of ShhN and the other through the Ca-mediated interface on ShhN. 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.

PubMed: 31127104
DOI: 10.1038/s41467-019-10234-9

Experimental method

ELECTRON MICROSCOPY (6.5 Å)