Structural basis for receptor selectivity and inverse agonism in S1P₅ receptors

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Sphingosine-1-phosphate (S1P) is a bioactive lipid that signals through five G protein-coupled receptors (S1P_1-5).
• S1P receptor subtype 5 (S1P₅) is crucial in immune cell trafficking and has implications in neurodegenerative diseases and cancer.
• Existing S1PR drugs lack subtype selectivity, causing adverse effects.

Purpose of the Study:

• To elucidate the structural basis of S1P₅ receptor activation and inverse agonism.
• To provide a structural template for developing subtype-selective S1PR modulators.

Main Methods:

• Serial femtosecond crystallography (SFX) at the Pohang Accelerator Laboratory X-Ray Free Electron Laser (PAL-XFEL).
• Determination of the 2.2 Å resolution room temperature crystal structure of human S1P₅ in complex with a selective inverse agonist.
• Analysis of structure-activity relationship (SAR) data.

Main Results:

• A unique ligand-binding mode for the S1P₅ receptor was identified, involving an allosteric sub-pocket.
• The determined structure clarifies the basis for S1P₅ receptor subtype selectivity.
• Structural insights into the mechanism of inverse agonism within the S1PR family were gained.

Conclusions:

• The S1P₅-inverse agonist structure provides a foundation for structure-based drug design targeting S1PRs.
• Understanding the structural determinants of inverse agonism can guide the development of safer and more effective S1PR-based therapeutics.
• This work enhances our comprehension of S1PR activation mechanisms.