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

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-S1 PR5).S1 PRs are widely distributed on many cell types,including cells in the cardiovascular,immune,and central nervous systems.1 The multi-functional 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 S1 PR family may assist in the development of drugs with improved safety profiles for the control of MS,cardiovascular and autoimmune disorders.