The sphingosine 1-phosphate (S1P) receptor signaling system has biological and medical importance, especially in the treatment of multiple sclerosis. S1P1 was the first lipid G protein-coupled receptor to be solved at 2.8A resolution . This lysophospholipid ligand binds to five high-affinity G protein-coupled receptors to generate multiple downstream signals that directly modulate homeostasis and pathology. ranging from vascular development, endothelial integrity, the control of cardiac rhythm, to treating multiple sclerosis. Understanding this integrated biochemical system has exemplified the impact of chemistry, genetics, and now structural biology. The S1P receptors have a novel N-terminal cap occluding access to the binding pocket from the extracellular environment. Good evidence for alternate binding mode and even allosteric agonists now exist, and the basis of sub-type selectivity is better understood. In addition, fluorescence-tagged receptor knock-in mice are now used to analyse integrated receptor function in physiology and pathology, and model pharmacodynamics. Causal relationships between protein expression, signal, and control points in physiology and pathology can now be directly understood.

Integrated chemical and structural biology of S1P1 therapeutics

245th National Meeting (2013)

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