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==Cryo-EM structure of the 2:1 hPtch1-Shhp complex==
==Cryo-EM structure of the 2:1 hPtch1-Shhp complex==
<StructureSection load='6n7h' size='340' side='right'caption='[[6n7h]], [[Resolution|resolution]] 3.60&Aring;' scene=''>
<SX load='6n7h' size='340' side='right' viewer='molstar' caption='[[6n7h]], [[Resolution|resolution]] 3.60&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6n7h]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N7H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6N7H FirstGlance]. <br>
<table><tr><td colspan='2'>[[6n7h]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N7H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6N7H FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.6&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6n7h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n7h OCA], [http://pdbe.org/6n7h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n7h RCSB], [http://www.ebi.ac.uk/pdbsum/6n7h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n7h ProSAT]</span></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6n7h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n7h OCA], [https://pdbe.org/6n7h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n7h RCSB], [https://www.ebi.ac.uk/pdbsum/6n7h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n7h ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/PTC1_HUMAN 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. [[http://www.uniprot.org/uniprot/SHH_HUMAN SHH_HUMAN]] Defects in SHH are the cause of microphthalmia isolated with coloboma type 5 (MCOPCB5) [MIM:[http://omim.org/entry/611638 611638]]. Microphthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, cataract and other abnormalities like cataract may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure).<ref>PMID:12503095</ref>  Defects in SHH are the cause of holoprosencephaly type 3 (HPE3) [MIM:[http://omim.org/entry/142945 142945]]. Holoprosencephaly (HPE) [MIM:[http://omim.org/entry/236100 236100]] is the most common structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of HPE3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. Interestingly, up to 30% of obligate carriers of HPE3 gene in autosomal dominant pedigrees are clinically unaffected.<ref>PMID:8896572</ref> <ref>PMID:9302262</ref> <ref>PMID:10441331</ref> <ref>PMID:10556296</ref> <ref>PMID:11479728</ref> <ref>PMID:15107988</ref> <ref>PMID:15221788</ref> <ref>PMID:15942952</ref> <ref>PMID:15942953</ref> <ref>PMID:16282375</ref> <ref>PMID:17001669</ref> <ref>PMID:19603532</ref>  Defects in SHH are a cause of solitary median maxillary central incisor (SMMCI) [MIM:[http://omim.org/entry/147250 147250]]. SMMCI is a rare dental anomaly characterized by the congenital absence of one maxillary central incisor.<ref>PMID:11471164</ref> <ref>PMID:15103725</ref>  Defects in SHH are the cause of triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:[http://omim.org/entry/174500 174500]]. TPTPS is an autosomal dominant syndrome characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. TPTPS mutations have been mapped to the 7q36 locus in the LMBR1 gene which contains in its intron 5 a long-range cis-regulatory element of SHH expression.<ref>PMID:12837695</ref> 
[https://www.uniprot.org/uniprot/PTC1_HUMAN 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 ==
== Function ==
[[http://www.uniprot.org/uniprot/PTC1_HUMAN 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.<ref>PMID:21537345</ref> [[http://www.uniprot.org/uniprot/SHH_HUMAN SHH_HUMAN]] Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. In the absence of SHH, PTC represses the constitutive signaling activity of SMO. Also regulates another target, the gli oncogene. Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction (By similarity).
[https://www.uniprot.org/uniprot/PTC1_HUMAN 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.<ref>PMID:21537345</ref>  
<div style="background-color:#fffaf0;">
== 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<ref>PMID:31127104</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6n7h" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Protein patched homolog 1|Protein patched homolog 1]]
*[[Sonic hedgehog 3D structures|Sonic hedgehog 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</SX>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Gong, X]]
[[Category: Gong X]]
[[Category: Qian, H W]]
[[Category: Qian HW]]
[[Category: Yan, N]]
[[Category: Yan N]]
[[Category: Protein binding]]
[[Category: Receptor]]
[[Category: Rnd family]]

Latest revision as of 14:13, 30 October 2024

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

6n7h, resolution 3.60Å

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