Sandbox Reserved 1172: Difference between revisions

LPA1 belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms form S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.