When an enemy invades, defenders are transported to the scene to neutralize the marauders. In the human body, a transporter protein called SPNS2 transports S1P molecules from endothelial cells to generate immune cell response in infected organs and tissues.
Using specially developed nanobodies that bind to SPNS2 and expand the entire structure, the expanded structure of SPNS2 allows S1P molecules to be observed by cryogenic electron microscopy. Scientists from the Immunology Translational Research Program at the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine) and their partners at the Harbin Institute of Technology, China, have analyzed the structure of the SPNS2 protein at the atomic level that They could provide more information about how S1P signaling molecules are released to communicate with immune cells and regulate inflammatory responses.
“Seeing is believing. This work shows that SPNS2 directly exports S1P for signaling and it is possible to inhibit its transport function with small molecules. This work provides the basis for understanding how SPNS2 releases S1P and how this protein function is inhibited by small molecules. for the treatment of inflammatory diseases,” said team leader Dr. Nguyen Nam Long.
The SPNS2 protein allows the binding of S1P signaling molecules to cause immune cells to leave the lymph nodes and induce inflammation in different parts of the body when necessary. Made up of amino acids, the SPNS2 protein is malleable enough to change its shape and structure to release S1P signaling molecules through small cavities found within the protein.
Thanks to the discovery of how the SPNS2 protein releases S1P molecules, the structure of SPNS2 can be exploited for future drug development. Similar to figuring out what the shape of the lock looks like before the key can be designed, this finding sheds more light on how future drugs can be designed to better target the protein and increase its effectiveness.
This finding builds on previous research that found that deleting the SPNS2 protein from a preclinical model effectively blocks the S1P signaling pathway, so that S1P signaling molecules cannot be transported to prompt immune cells to leave the lymph node to induce inflammation. Both the SPNS2 protein and the S1P signaling molecule are required for the recruitment of immune cells to inflammatory organs, which is used to treat various inflammatory diseases.
“Using preclinical models, we have shown that targeting SPNS2 proteins in the body blocks inflammatory responses in diseases such as multiple sclerosis. This work has given us the possibility of inhibiting its transport function with small molecules that will go a long way in treating diseases.” more efficiently and effectively,” said Dr. Nguyen.