Cell Res :重大进展!王明伟/徐华强/张岩联手合作,揭示GLP-2R独特的激素识别功能

2020-11-26 枫叶 iNature

胰高血糖素样肽(GLP-1和GLP-2)是两种胰高血糖素衍生的肠道激素,它们通过两个相关受体(GLP-1R和GLP-2R)介导不同的生理功能,这两个受体分别是代谢紊乱和克罗恩病的重要药物靶标。

胰高血糖素样肽(GLP-1和GLP-2)是两种胰高血糖素衍生的肠道激素,它们通过两个相关受体(GLP-1R和GLP-2R)介导不同的生理功能,这两个受体分别是代谢紊乱和克罗恩病的重要药物靶标。尽管在GLP-1R结构测定方面取得了巨大进展,但对这两种受体之间的肽结合和信号转导差异的了解仍然难以捉摸。

2020年11月25日, 中国科学院上海药物研究所王明伟,徐华强及浙江大学张岩共同通讯在Cell Research 在线发表题为“A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor”的研究论文,该研究报告人类GLP-2R与GLP-2和Gs异源三聚体复合的冷冻电子显微镜结构。

为了适应GLP-2而不是GLP-1,GLP-2R会微调跨膜螺旋(TMs)和细胞外环1(ECL1)的细胞外部分的构象。与GLP-1相反,GLP-2的N端组氨酸以独特的方向渗透到受体核中。GLP-2的中间区域与TM1和TM7的结合比与ECL2的结合更广泛,并且GLP-2 C末端与ECL1紧密相连,ECL1在9类B G蛋白偶联受体(GPCR)中最突出。功能研究表明,GLP-2的上述三个部分对于GLP-2识别和受体激活(尤其是中间区域)至关重要。这些结果为B类GPCR中配体特异性的分子基础提供了新的见识,并可能促进更特异性疗法的发展。

GLP-2R属于B类GPCR亚家族,主要在肠,胰腺和脑中表达。其内源性配体是胰高血糖素样肽家族的成员GLP-2,其也包括GLP-1和胰高血糖素。GLP-2由前胰高血糖素基因编码,并在前激素转化酶进行翻译后加工后变得有活性。作为胃肠激素,它主要调节肠上皮细胞的生长和功能,对营养的吸收至关重要。与GLP-1类似,GLP-2在体内被二肽基肽酶迅速灭活。

临床上,GLP-2类似物,teduglutide,用于治疗短肠综合征和克罗恩氏病。目前正在开发其他治疗适应症,包括结肠炎,小儿胃肠道疾病和肠粘膜炎症。动物模型的最新研究表明,GLP-2对葡萄糖稳态,自发性高血压和抑郁症有至关重要的作用,这促使人们重新关注这种肽在胃肠道之外的作用。

冷冻电子显微镜(cryo-EM)是确定GPCR-G蛋白复合物结构的主要方法,从GLP-1R和降钙素受体开始,随后是八种其他B类GPCR与各种G蛋白复合物。这些结构表明B类GPCR具有共同的激活模式,该模式与先前提出的两结构域结合模型基本吻合。尽管B类受体具有大致相同的激活模式,分子细节是受体特异性的,尤其是在配体结合区域。因此,探索GLP-2和GLP-2R之间的识别机制对于进一步了解B类GPCR之间的配体识别和受体激活机制具有重要意义。

在这项研究中,采用cryo-EM来确定与Gs蛋白复合的人GLP-2R的高分辨率结构。根据的先前经验,NanoBiT策略被用于稳定GLP-2–GLP-2R–Gs复合物并增强GLP-2R与Gβ之间的相互作用,从而在整体范围内形成了一个冷冻EM结构,分辨率为3.0?。该研究数据提供了一个合理的模板,可促进设计更好的GLP-2类似物用于治疗,并扩展对该受体家族生物学的认识。

原始出处:

Wen Sun, Li-Nan Chen, Qingtong Zhou, et al.A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor.Cell Research (2020)Published: 25 November 2020

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