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%. <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. 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 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: Electrostatic illustration of the amphipathic binding pocket of the LPA₁ receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]