配体识别和激活黑色素浓缩激素受体的机制。

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-05-07 DOI:10.1038/s41421-024-00679-8
Qian He, Qingning Yuan, Hong Shan, Canrong Wu, Yimin Gu, Kai Wu, Wen Hu, Yumu Zhang, Xinheng He, H Eric Xu, Li-Hua Zhao
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摘要

黑色素浓缩激素(MCH)是一种环状神经肽,通过刺激 MCHR1 和 MCHR2 受体来调节食物摄入量、能量平衡和其他生理功能,这两种受体都是 A 类 G 蛋白偶联受体。MCHR1 主要与抑制性 G 蛋白 Gi/o 结合,而 MCHR2 只能与 Gq/11 结合。这里我们展示了 MCH 激活的 MCHR1 与 Gi 和 MCH 激活的 MCHR2 与 Gq 的冷冻电镜结构,其全局分辨率分别为 3.01 Å 和 2.40 Å。这些结构显示,当 MCH 与这两种受体结合时,其半胱氨酸介导的发夹环构型是一致的。在 MCH 的两个半胱氨酸之间,来自 LGRVY 核心基团的中央精氨酸深入跨膜袋,引发受体活化。结合突变和功能方面的见解,我们的发现阐明了配体识别和 MCH 受体激活的分子基础,并为靶向药物设计提供了结构基础。
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Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors.

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 and MCHR2 receptors, both of which are class A G protein-coupled receptors. MCHR1 predominately couples to inhibitory G protein, Gi/o, and MCHR2 can only couple to Gq/11. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with Gi and MCH-activated MCHR2 with Gq at the global resolutions of 3.01 Å and 2.40 Å, respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration when bound to both receptors. A central arginine from the LGRVY core motif between the two cysteines of MCH penetrates deeply into the transmembrane pocket, triggering receptor activation. Integrated with mutational and functional insights, our findings elucidate the molecular underpinnings of ligand recognition and MCH receptor activation and offer a structural foundation for targeted drug design.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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