S1PR1
October 2022
Sphingosine-1-phosphate receptor type 1
There is a bonus at the very bottom of the article, so be sure to read to the very end.
Sphingosine-1-phosphate receptor type 1 (S1PR1) is a G-protein-coupled receptor (GPCR) that natively binds to the bioactive lipid S1R. S1PR1 plays a critical role in the regulation of the immune system and is therefore an attractive pharmacological target for autoimmune diseases.
For example, several FDA-approved drugs are targeting S1PR1 for the treatment of multiple sclerosis (MS), a chronic, inflammatory, autoimmune disease of the central nervous system. These drugs activate the receptor and stimulate its association with β-arrestin (a phenomenon also known as “biased-agonism”). This induces the internalization and degradation of the receptor, resulting in attenuation of the inflammatory response.
However, even if the therapeutic action is very well understood, the structural basis of biased agonism is still elusive.
In a recent paper from academia, the authors solved the cryo-EM structure of S1PR1 in a complex with its biased agonist, siponimod (BAF312, Novartis) - a drug used for the treatment of MS. When they compared it with the structure of S1PR1 in its inactive state, they were able to give a structural explanation for the observed biased agonism and provide a rational basis for the design of novel biased S1PR1 modulators.
The structure they used as a reference was a complex of S1PR1 with an antagonist (ML056), which stabilizes the inactive conformation of the receptor. Upon binding with the biased agonist siponimod, S1PR1 shows a very different 3D structural arrangement. In the ligand binding pocket, in particular, many residues occupy different positions when siponimod is bounded because of its bigger dimensions compared to the antagonist. The lateral chains of residues L128, F210, F273, and W269 are forced to flip to accommodate siponimod (Image 1), and this causes a cascade of structural rearrangements along the protein, which results in a favored β-arrestin interaction.
Image 1. The agonist siponimod (in yellow) bound to S1PR1 (in pink, PDB ID: 7EO4) superimposed to the same receptor in complex with an antagonist (in grey, PDB ID: 3V2Y). The differences between the two structures are highlighted using Pocket highlight mode, 3decision software.
They confirmed their hypothesis observing that ligands with a similar molecular shape to siponimod, produced the same β-arrestin biased activity. This crucial finding will greatly contribute to the rational design of new, biased, and more specific drugs targeting S1PR1.
BONUS
With 3decision you can easily explore GPCRs 3D structures using the Annotation Browser. It allows you to quickly localize a residue on the 3D structure using the Ballesteros–Weinstein numbering scheme - as shown in the video below.