Structural Insights into Sphingosine-1-phosphate Receptor Activation

Abstract

As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1-5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or non-lipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its non-redundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here we reported four atomic resolution cryo-EM structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod ((S)-FTY720-P), or non-lipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step "shallow to deep" transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1P receptors.

Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation

“…All LysoGPs are zwitterionic molecules with a negatively charged head and a highly hydrophobic acyl tail, and many of them serve as signaling molecules to regulate a broad spectrum of physiologies via binding to GPCRs. We, therefore, asked whether the receptor binding modes of LysoGPs are similar by comparing recently solved lysophospholipid receptors including S1P-bound S1PR1/G i complex 21 , LPA-bound LPAR1/G i complex 17 and monoolein-bound zebrafish LPAR6a crystal structure 20 . A superimposition of these receptors with LysoPS-bound GPR174 shows that S1PR1 and LPAR1, both of which belong to the EDG lipid receptor family 22 , have similar receptor binding modes, the phosphate heads of them stand up and point to the extracellular side, forming polar interactions with the conserved tyrosine and lysine of the N-terminal Helix (Fig.…”

Inflammatory bowel disease and immune-mediated inflammatory diseases: looking at the less frequent associations

“…148,152,153 On the other hand, the only advanced therapy that may have a role in both diseases is the class of the sphingosine-1 receptor modulator, which are still on study for IBD. 154 Thus, to date, given the harmless nature of vedolizumab on demyelinating diseases, a possible option is to treat IBD with this drug and MS with a separate target therapy, if needed. 155 Another particular clinical picture is that of the so-called 'radiologically isolated MS', that is journals.sagepub.com/home/tag…”

Adverse effect of FTY720P on colonic Na+/K+ ATPase is mediated via ERK, p38MAPK, PKC, and PI3K

“…FTY720P or fingolimod phosphate, an active immune modulator (Yu et al, 2022), has been recognized as a structural analogue of sphingosine 1‐phosphate (S1P). It has been approved by the Food and Drug Administration for the treatment of multiple sclerosis and showed promising results in the treatment of cancer (White et al, 2016).…”