Exploration of LPS agonist binding modes using the combination of a new hydrophobic scaffold and homology modeling.

Lysophosphatidylserine (LysoPS) is an endogenous pan-agonist of three G-protein coupled receptors (GPCRs): LPS/GPR34, LPS/P2Y, and LPS/GPR174, and we previously reported a series of LysoPS-based agonists of these receptors. Interestingly, we found that LPS agonist activity was very sensitive to structural change at the hydrophobic fatty acid moiety, whereas LPS agonist activity was not. Here, to probe the molecular basis of LPS agonist binding, we developed a new class of hydrophobic fatty acid surrogates having a biphenyl-ether scaffold.