Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition

Yuan, Yuan; Jia, Guowen; Wu, Chao; Wang, Wei; Cheng, Lin; Li, Qian; Li, Ziyan; Luo, Kaidong; Yang, Shengyong; Yan, Wei; Su, Zhaoming; Shao, Zhenhua

doi:10.1038/s41422-021-00566-x

Cited by 64 publications

(84 citation statements)

References 58 publications

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“…Also, two recent publications reported the cryo-EM structures of the complexes of S1P 1 -G i , S1P 5 -G i and S1P 3 -Gi (Supplementary Fig. 13b) 37,38 . Upon activation, F210 in S1P 1 rotates away from the side pocket to create extended trefoil space for long straight ligand to be accommodated (Fig.…”

Section: Discussionmentioning

confidence: 98%

Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate

et al. 2022

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Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The mechanisms of lysophospholipid recognition by an active GPCR, and the activations of lysophospholipid GPCR–G-protein complexes remain unclear. Here we report single-particle cryo-EM structures of human S1P receptor 1 (S1P1) and heterotrimeric Gi complexes formed with bound S1P or the multiple sclerosis (MS) treatment drug Siponimod, as well as human LPA receptor 1 (LPA1) and Gi complexes in the presence of LPA. Our structural and functional data provide insights into how LPA and S1P adopt different conformations to interact with their cognate GPCRs, the selectivity of the homologous lipid GPCRs for S1P versus LPA, and the different activation mechanisms of these GPCRs by LPA and S1P. Our studies also reveal specific optimization strategies to improve the MS-treating S1P1-targeting drugs.

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Section: Discussionmentioning

confidence: 98%

Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate

et al. 2022

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“…S11B) and the four structures reported by Shao group ( SI Appendix , Fig. S11C)(29). With the analysis of CBP-307 binding modes and the conformational change of G protein complexes, we propose a two-step model of S1PR1 activation by CBP-307.…”

Section: Resultsmentioning

confidence: 68%

“…S1PR1, with different agonists bound at the extracellular side and G i complex bound at the intracellular side, demonstrate an active state super-complex, which is reminiscent of the structures of other G i -coupled class A GPCRs (29, 31). The structural analysis reflects some common features for other lipid receptors, such as cannabinoid receptors (32) and CRTH2 (33).…”

Section: Resultsmentioning

confidence: 81%

“…However, the detailed mechanism of CBP-307 selectivity is still poorly understood. We compared CBP-307 bound S1PR1-G i structure (deep mode) to Siponimod bound S1PR5-G i and the d18:1 S1P bound S1PR3-G i structures reported by Shao group (29, 30). Residues composed of the orthosteric binding pocket of S1PR1 and S1PR5 are highly conserved ( SI Appendix , Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The inactive structure of S1PR1 bound with an antagonist was reported in 2012 (27). Recently, the crystal structure of active S1PR3 bound to Fab and endogenous agonist S1P and active state structures of S1PR1,3,5 bound to Gi complex and different agonists were reported (28)(29)(30). Here we reported four atomic resolution cryo-EM structures of Gi-coupled human S1PR1 complexes bound to d18:1 S1P, (S)-FTY720-P, or CBP-307 in two binding modes.…”

Section: Introductionmentioning

confidence: 99%

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Structural Insights into Sphingosine-1-phosphate Receptor Activation

Gan

et al. 2022

Preprint

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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.

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Structural determinants of sphingosine‐1‐phosphate receptor selectivity

Wunsch,

Nguyen,

Wolber

et al. 2023

Archiv der Pharmazie

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Fingolimod, the prodrug of fingolimod‐1‐phosphate (F1P), was the first sphingosine‐1‐phosphate receptor (S1PR) modulator approved for multiple sclerosis. F1P unselectively targets all five S1PR subtypes. While agonism (functional antagonism via receptor internalization) at S1PR1 leads to the desired immune modulatory effects, agonism at S1PR3 is associated with cardiac adverse effects. This motivated the development of S1PR3‐sparing compounds and led to a second generation of S1PR1,5‐selective ligands like siponimod and ozanimod. Our method combines molecular dynamics simulations and three‐dimensional pharmacophores (dynophores) and enables the elucidation of S1PR subtype‐specific binding site characteristics, visualizing also subtle differences in receptor–ligand interactions. F1P and the endogenous ligand sphingosine‐1‐phosphate bind to the orthosteric pocket of all S1PRs, but show different binding mode dynamics, uncovering potential starting points for the development of subtype‐specific ligands. Our study contributes to the mechanistic understanding of the selectivity profile of approved drugs like ozanimod and siponimod and pharmaceutical tool compounds like CYM5541.

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Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition

Cited by 64 publications

References 58 publications

Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate

Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate

Structural Insights into Sphingosine-1-phosphate Receptor Activation

Structural determinants of sphingosine‐1‐phosphate receptor selectivity

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