Volume 32, No 2, Feb 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 2, February 2022: 218-221

LETTERS TO THE EDITOR

Structural insights into sphingosine-1-phosphate recognition and ligand selectivity of S1PR3–Gi signaling complexes

Chang Zhao^1,† , Lin Cheng^1,† , Wei Wang^1,† , Heli Wang^1,† , Yongbo Luo¹ , Yuying Feng¹ , Xuehui Wang¹ , Hong Fu¹ , Ye Cai¹ , Shengyong Yang¹ , Ping Fu¹ , Wei Yan^1,* , Zhenhua Shao^1,*

¹Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
^†These authors contributed equally: Chang Zhao, Lin Cheng, Wei Wang, Heli Wang
Correspondence: Wei Yan(weiyan2018@scu.edu.cn)Zhenhua Shao(zhenhuashao@scu.edu.cn)

Dear Editor,

Lipids are essential for all life on earth and play critical roles in energy storage and the formation of cellular membranes. Sphingosine-1-phosphate (S1P) is a naturally occurring bioactive lysophospholipid that regulates fundamental physiological processes by activating five G protein-coupled receptors (S1PR1–S1PR5). S1PRs are widely distributed on many cell types, including cells in the cardiovascular, immune, and central nervous systems.1 The multifunctional S1P-S1PR signaling is a driver of multiple diseases and S1PR1-targeted drugs have been approved as therapeutic strategies for the treatment of multiple sclerosis (MS) and autoimmune disorders. The first approved drug fingolimod (FTY720), after in-vivo phosphorylation to pFTY720, has cross reactivity with the S1PR family (S1PR1–3 and S1PR5), and subtype-selective modulators have been pursued as potential therapeutics. Siponimod is selective for S1PR1 and S1PR5 and has been approved for the treatment of secondary progressive MS. Molecules that lack S1PR3-targeting activity may be a useful strategy for the development of S1PR1 agonist drugs.2 Therefore, understanding the mechanism of S1P-S1PR signaling and identifying differences in the ligand selectivity of the S1PR family may assist in the development of drugs with improved safety profiles for the control of MS, cardiovascular and autoimmune disorders.

https://doi.org/10.1038/s41422-021-00567-w

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