| - | Sphingolipids together with glycerol-based phospholipids are major structural components of cell membranes. In response to various extracellular stimuli, including growth factors, inflammatory cytokines, antigens, and agonists of some GPCRs, the sphingolipids can be metabolized into potent mediators, such as [[Sphingosine-1-phosphate (S1P)]]. This sphingolipid has emerged as an important signaling mediator participating in the regulation of multiple physiological and pathological processes taking place in cancer, cardiovascular diseases, wound healing, atherosclerosis and asthma but also is important in pathological conditions such as inflammation and stress. It can also trigger a range of biological effects such as cell migration, differentiation, apoptosis, immunity, proliferation and angiogenesis. The functioning of S1P receptors in the maintenance and modulation of the activity of the biological barrier is of the profound biological importance and has many therapeutic implications including treatment of multiple sclerosis, prevention of the transplant rejection and probably the adult respiratory distress syndrome as well.
| + | *[[User:Harish Srinivas/Sandbox 1]] |
| - | After binding of agonist S1P to the binding site of S1P1, the movement of acyl tail of S1P leads to the flipping of W2696.48 (step 1). Such rotameric change alters the conformation of side chain of F265 which is located next to W2696 in the same helix TM6 (step 2). These residues form a core of a transmission switch which involves rearrangement of centrally located residues including N63, D91, S304 and N307 They facilitate a redirected flow of water molecules inside a receptor (step 3). The influx of water molecules at intracellular part of the receptor leads to limited motions of cytoplasmic ends of TM helices, with the largest movement associated with TM7 (step 4), which is a prerequisite for larger motions of the cytoplasmic parts of transmembrane helices. These movements lead to opening the protein structure to make room for binding a G protein. The mutations of S1P1 receptor analyzed so far were located close to the orthosteric binding site of native agonist S1P.
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