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 3). <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 in LPA₁, 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 from ECL0 lack of secondary structure in LPA₁ further promotes favorable LPA access to the binding pocket from the extracellular space. <ref name="regpeps">PMID: 26091040</ref>

LPA₁ is also closely related to the first of the six [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB₁ ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and LPA₁ the ability to bind to analogs of CB₁ ligands. <ref name="regpeps">PMID: 26091040</ref> This crossing over of ligand binding opens the possibility of metabolic crosstalk between the two signaling systems. <ref name="regpeps">PMID: 26091040</ref> Complementary access to the LPA₁ binding pocket can be achieved by phosphorylated CB₁ ligand analogs, while complementary access to the CB₁ binding site requires dephosphorylation of LPA₁ ligand analogs (Figure 4). In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor. <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, including the ligand LPA. The polarity of these residues provide favorable interactions between the ligand and the binding pocket.<ref name="regpeps">PMID: 26091040</ref> Additionally, Asp129 and Trp210 may serve as a trigger for agonist induced conformational changes. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> 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 lead to the expansion of the binding pocket and the exposure of the π clouds of their indole rings. These shifts and expansion provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands (Figure 5). This favorable binding provided 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>