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Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA₁) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA₁-LPA₆) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>. LPA₁ is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family] which includes the more widely known sphingosine 1-phopshate receptors.

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 is 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 <ref name="regpeps">PMID: 26091040</ref>. 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 from S1P₁ <ref name="regpeps">PMID: 26091040</ref>. 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 <ref name="regpeps">PMID: 26091040</ref>.

<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA₁ may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution (reference). Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref>.

A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB₁'s most abundant endogenous ligands into the LPA₁ binding pocket <ref name="regpeps">PMID: 26091040</ref>. Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA₁ and CB₁ are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups <ref name="regpeps">PMID: 26091040</ref>.