7urc
Human PORCN in complex with LGK974
Structural highlights
DiseasePORCN_HUMAN Focal dermal hypoplasia;Colobomatous microphthalmia. The disease is caused by variants affecting the gene represented in this entry. FunctionPORCN_HUMAN Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins. Serine palmitoleoylation of WNT proteins is required for efficient binding to frizzled receptors.[UniProtKB:Q9JJJ7][1] [2] [3] Publication Abstract from PubMedWnt 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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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