Cell Research, 14 May, 2024, DOI：https://doi.org/10.1038/s41422-024-00968-7

Molecular activation and G protein coupling selectivity of human succinate receptor SUCR1

Tianxin Wang, Wenqin Tang, Xiaolei Zhu, Zhenyu Lv, Jiayan Chen, Yongze Li, Xiaoyu Sun, Haoyu Lv, Quanchang Gu, Fahui Li & Jiangyun Wang

Abstract

Succinate (SA) is a classic intermediate metabolite of the TCA cycle and is produced in mitochondria under normal physiological conditions. SA accumulates within cells and is secreted into the extracellular space, engaging in metabolic regulation and inflammatory response during conditions such as hypoxia, ischemia-reperfusion, and pro-inflammatory processes. Excess SA functions as a paracrine signal through its extracellular G protein-coupled receptor, SUCR1, which senses extracellular metabolic stress signals and regulates energy homeostasis. SUCR1 couples to G_i and G_q signaling pathways, resulting in physiological effects closely tied to human health and diseases such as hypertension, diabetes, inflammation, atherosclerosis, sepsis, immune response, cancer, asthma, and adiposity. Therefore, it is of great interest as a drug target. While the crystal structure of antagonist-bound rat SUCR1 complex has been resolved to clarify the inactivation mechanism of the receptor, a comprehensive understanding of the detailed molecular activation mechanism triggered by SA sensation is impeded by the lack of experimental active-state SUCR1 structures.

Article link：https://www.nature.com/articles/s41422-024-00968-7