小柯机器人

美国德州大学西南医学中心Xiaochun Li团队近期取得重要工作进展，他们研究发现了Porcupine介导的Wnt酰化的机制和抑制作用。相关论文2022年7月13日在线发表于《自然》杂志上。

在这里，研究人员报告了人类PORCN的四种低温电子显微镜结构：与棕榈油酰辅酶A（palmitoleoyl-CoA）底物的复合物；与PORCN抑制剂LGK974的复合物，这是一种目前处于临床试验阶段的抗癌药物；具有LGK974和WNT3A发夹2（WNT3Ap）的复合物；以及与合成的棕榈油酰化WNT3Ap类似物的复合物。

这些结构表明，在所有Wnt配体中都非常保守的WNT3A的发夹2从管腔侧插入PORCN，而棕榈油酰辅酶A从胞质侧进入酶。催化组氨酸触发不饱和棕榈油酰基转移到Wnt发夹2上的目标丝氨酸上，这得益于两个底物的接近。抑制剂结合结构表明LGK974占据了棕榈油酰辅酶A结合位点以阻止反应。因此，这项工作为Wnt酰化提供了一种机制，并推动了用于癌症治疗的PORCN抑制剂的开发。

据了解，Wnt信号传导对胚胎发育和成人组织稳态的调控至关重要，而异常的Wnt信号传导通常与癌症相关。Wnt信号需要通过内质网驻留膜结合的O-酰基转移酶Porcupine（PORCN）对发夹2基序进行棕榈烯酰化。这种修饰对于Wnt与其受体Frizzled的结合是必不可少的，而Frizzled会触发信号传导。

附：英文原文

Title: Mechanisms and inhibition of Porcupine-mediated Wnt acylation

Author: Liu, Yang, Qi, Xiaofeng, Donnelly, Linda, Elghobashi-Meinhardt, Nadia, Long, Tao, Zhou, Rich W., Sun, Yingyuan, Wang, Boyuan, Li, Xiaochun

Issue&Volume: 2022-07-13

Abstract: Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis1,2,3, and aberrant Wnt signalling is frequently associated with cancers4. Wnt signalling requires palmitoleoylation on a hairpin 2 motif by the endoplasmic reticulum-resident membrane-bound O-acyltransferase Porcupine5,6,7 (PORCN). This modification is indispensable for Wnt binding to its receptor Frizzled, which triggers signalling8,9. 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 trials10; 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.

DOI: 10.1038/s41586-022-04952-2

Source: https://www.nature.com/articles/s41586-022-04952-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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