Structural insights into sphingosine-1-phosphate receptor activation.

Area of Science:

• Biochemistry
• Structural Biology
• Immunology

Background:

• Sphingosine-1-phosphate (S1P) is a vital sphingolipid metabolite regulating immune and vascular functions.
• S1P receptors (S1PRs), particularly S1PR1, are crucial for lymphocyte trafficking and represent therapeutic targets.
• The precise structural mechanisms of S1PR1 activation by diverse agonists are not fully understood.

Purpose of the Study:

• To elucidate the atomic resolution structural basis of human S1PR1 activation by endogenous S1P, a lipid-like mimic, and a non-lipid-like therapeutic molecule.
• To understand the distinct binding modes and activation mechanisms of S1PR1 conferred by different ligand types.
• To provide a structural foundation for the rational design of S1PR1-targeting therapeutics.

Main Methods:

• Atomic resolution cryo-electron microscopy (cryo-EM) to determine structures of human S1PR1 complexes.
• Biochemical analyses to investigate receptor activation and signaling.
• Molecular dynamic simulations to explore ligand binding and receptor dynamics.

Main Results:

• Four cryo-EM structures of Gi-coupled human S1PR1 complexes were determined with S1P, (S)-FTY720-P, and CBP-307.
• Identified similarities and differences in S1PR1 activation driven by distinct agonists binding to the orthosteric pocket.
• Proposed a two-step "shallow to deep" binding transition for CBP-307, potentially enhancing Gαi coupling and membrane interaction.

Conclusions:

• The study deciphers common features of S1PR1 agonist recognition and activation mechanisms at an atomic level.
• Structural insights into S1PR1 activation by diverse ligands will accelerate the development of novel therapeutics.
• Understanding S1PR1 structural dynamics is critical for modulating immune cell trafficking and vascular integrity.