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 shares many structural similarities to LPA₁. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. The hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P₁ via the membrane. LPA₁ differs and utilizes an extracellular opening that allows LPA access from the extracellular space (Figure 2). <ref name="regpeps">PMID: 26091040</ref> Structural evidence for this altered ligand binding pathway includes global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, a slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 Å 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 Å from S1P₁ result in ligand access via the extracellular space. <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 for LPA₁. Additionally, ECL0 is helical in S1P₁, but <scene name='72/721543/Ecl02ndstructure/1'>lacks secondary structure</scene> in LPA₁. This increased flexibility that results further promotes favorable access from the extracellular space. <ref name="regpeps">PMID: 26091040</ref>

[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 1: Extracellular ligand access pathway on LPA₁. Compared to S1P₁, ECL3 shown in red is positioned 8 Å further from ECL0 and ECL2 shown in green. This largely contributes to the altered ligand binding pathway between LPA₁, and S1P₁]]

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>

[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 1: Illustration of key LPA₁ binding pocket residues Trp210 and Trp271. These residues provide rotameric shifts and expansion that allow for favorable interactions with phosphorylated cannabinoid ligands.]]