View source for 7urf


==Human HHAT H379C in complex with SHH N-terminal peptide==
<StructureSection load='7urf' size='340' side='right'caption='[[7urf]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7urf]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7URF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7URF FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AJP:(25R)-2beta,15alpha-dihydroxy-5beta,8alpha,10alpha,14beta,17beta-spirostan-3alpha-yl+beta-D-glucopyranosyl-(1- 3)-beta-D-galactopyranosyl-(1- 2)-[beta-D-xylopyranosyl-(1- 3)]-beta-D-glucopyranosyl-(1- 4)-beta-D-galactopyranoside'>AJP</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=PKZ:PALMITOYL-COA'>PKZ</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=7urf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7urf OCA], [https://pdbe.org/7urf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7urf RCSB], [https://www.ebi.ac.uk/pdbsum/7urf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7urf ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/HHAT_HUMAN HHAT_HUMAN] Chondrodysplasia-difference of sex development syndrome. The disease is caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/HHAT_HUMAN HHAT_HUMAN] Palmitoyl acyltransferase that catalyzes N-terminal palmitoylation of SHH; which is required for SHH signaling (PubMed:18534984, PubMed:24784881, PubMed:31875564). It also catalyzes N-terminal palmitoylation of DHH (PubMed:24784881). Promotes the transfer of palmitoyl-CoA from the cytoplasmic to the luminal side of the endoplasmic reticulum membrane, where SHH palmitoylation occurs (PubMed:31875564). It is an essential factor for proper embryonic development and testicular organogenesis (PubMed:24784881).<ref>PMID:11486055</ref> <ref>PMID:18534984</ref> <ref>PMID:24784881</ref> <ref>PMID:31875564</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis(1-3), and aberrant Wnt signalling is frequently associated with cancers(4). Wnt signalling requires palmitoleoylation on a hairpin 2 motif by the endoplasmic reticulum-resident membrane-bound O-acyltransferase Porcupine(5-7) (PORCN). This modification is indispensable for Wnt binding to its receptor Frizzled, which triggers signalling(8,9). Here we report four cryo-electron microscopy structures of human PORCN: the complex with the palmitoleoyl-coenzyme A (palmitoleoyl-CoA) substrate; the complex with the PORCN inhibitor LGK974, an anti-cancer drug currently in clinical trials(10); the complex with LGK974 and WNT3A hairpin 2 (WNT3Ap); and the complex with a synthetic palmitoleoylated WNT3Ap analogue. The structures reveal that hairpin 2 of WNT3A, which is well conserved in all Wnt ligands, inserts into PORCN from the lumenal side, and the palmitoleoyl-CoA accesses the enzyme from the cytosolic side. The catalytic histidine triggers the transfer of the unsaturated palmitoleoyl group to the target serine on the Wnt hairpin 2, facilitated by the proximity of the two substrates. The inhibitor-bound structure shows that LGK974 occupies the palmitoleoyl-CoA binding site to prevent the reaction. Thus, this work provides a mechanism for Wnt acylation and advances the development of PORCN inhibitors for cancer treatment.

Mechanisms and inhibition of Porcupine-mediated Wnt acylation.,Liu Y, Qi X, Donnelly L, Elghobashi-Meinhardt N, Long T, Zhou RW, Sun Y, Wang B, Li X Nature. 2022 Jul;607(7920):816-822. doi: 10.1038/s41586-022-04952-2. Epub 2022 , Jul 13. PMID:35831507<ref>PMID:35831507</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7urf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Li X]]
[[Category: Liu Y]]
[[Category: Qi X]]