Biophysicists from the Center for Research on Molecular Mechanisms of Aging and Age-Related Diseases of the Moscow Institute of Physics and Technology, together with foreign colleagues, have revealed the features of the receptor, which plays an important role in immune and neurodegenerative disorders, as well as in carcinogenesis. They studied the functioning of the S1P receptors (five members of the sphingosine-1-phosphate receptor family).
Current drugs for the treatment of multiple sclerosis, Crohn's disease and other autoimmune diseases that target S1P receptors are not sufficiently selective in receptor subtypes and mechanisms of action, leading to side effects. The researchers decided to study their interaction with receptors at the molecular level, and for this it was necessary to better understand the structure and mechanisms of the receptors themselves.
Biophysicists from the Moscow Institute of Physics and Technology examined the crystal structure of the S1P5 receptor using serial femtosecond crystallography (SFX) on an X-ray free electron laser (XFEL).
Classical X-ray crystallography implies irradiation of one crystal from different sides and joint analysis of scattering patterns. With SFX, the crystal is destroyed immediately, but its diffraction pattern appears on the detector earlier. As a result, the researchers needed to sequentially irradiate many small crystals and analyze a large series of diffraction patterns.
As a result, they obtained for the first time the structure of an important G-protein-coupled receptor. This allows you to create templates for the search for selective therapeutic drugs with a targeted function and a minimum number of side effects.
The information obtained can be used for computer-aided drug development, which will speed up the process of creating drugs.
During the project, scientists created and tested genetically engineered constructs, expressed and isolated the receptor, crystallized and determined its structure by X-ray diffraction analysis using X-ray free electron laser (XFEL) at the Pohang City Accelerator Laboratory (PAL-XFEL) in South Korea. Then, the resulting structure was subjected to computer simulation and molecular docking.
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