6n7h

From Proteopedia

Cryo-EM structure of the 2:1 hPtch1-Shhp complex

6n7h, resolution 3.60Å

Structural highlights

6n7h is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.6Å
Ligands:
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PTC1_HUMAN Semilobar holoprosencephaly;Monosomy 9q22.3;Alobar holoprosencephaly;Microform holoprosencephaly;Septopreoptic holoprosencephaly;Gorlin syndrome;Lobar holoprosencephaly;Midline interhemispheric variant of holoprosencephaly. The disease may be caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

PTC1_HUMAN Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis.^[1]

Publication Abstract from PubMed

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 Ca(2+)-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.

Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm.,Qian H, Cao P, Hu M, Gao S, Yan N, Gong X Nat Commun. 2019 May 24;10(1):2320. doi: 10.1038/s41467-019-10234-9. PMID:31127104^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ma G, Yu J, Xiao Y, Chan D, Gao B, Hu J, He Y, Guo S, Zhou J, Zhang L, Gao L, Zhang W, Kang Y, Cheah KS, Feng G, Guo X, Wang Y, Zhou CZ, He L. Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels. Cell Res. 2011 Sep;21(9):1343-57. doi: 10.1038/cr.2011.76. Epub 2011 May 3. PMID:21537345 doi:http://dx.doi.org/10.1038/cr.2011.76
↑ 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. 2019 May 24;10(1):2320. doi: 10.1038/s41467-019-10234-9. PMID:31127104 doi:http://dx.doi.org/10.1038/s41467-019-10234-9