Sandbox Reserved 1172: Difference between revisions
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LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. 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>. | LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. 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 LPA<sub>1</sub> 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. | <scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> 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 CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> 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 LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups <ref name="regpeps">PMID: 26091040</ref>. | A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> 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 LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups <ref name="regpeps">PMID: 26091040</ref>. | ||
