Sandbox Reserved 1174: Difference between revisions

The LPA₁ receptor consists of seven transmembrane alpha helices. It lies in the membrane as shown in Figure 2, and as shown by the <scene name='72/721545/Membrane/6'>fatty acid</scene> bound in the crystallization of LPA₁ in orange. Most <scene name='72/721545/Polarity/4'>polar amino acids</scene> (red) reside on the intracellular and extracellular areas of the receptor, while most residues positioned on the trans membrane helices inside the membrane are hydrophobic (blue). A cytochrome b (b₅₆₂RIL) protein was inserted into the third intracellular loop to facilitate crystallization (Figure 2). The intracellular region of this membrane protein is coupled to a [https://www.ebi.ac.uk/interpro/potm/2004_10/Page2.htm heterotrimeric G protein].

Three native <scene name='72/721545/Disulfides/5'>disulfide bonds</scene> in the extracellular region of this receptor provide fold stability.<ref name= "Chrencik"/> The first disulfide bond constrains the N terminal helix to extracellular loop(ECL) 2. The second disulfide bond shapes ECL2, and the third binds ECL3 to one of the transmembrane alpha helices. These disulfide bonds provide intramolecular stabilization along the extracellular region of the LPA₁ receptor, where the substrate enters into the binding pocket. The <scene name='72/721545/N-terminus/3'>N-terminus</scene> is a six turn alpha helix. It functions like a cap on the extracellular side of the protein, packing tightly against ECL1 and ECL2. The N-terminus helix also provides <scene name='72/721545/34_39_40/4'>polar amino acids</scene> that interact with the ligand when bound. The extracellular region of this receptor plays a role in substrate specificity.  

Lysophosphatidic Acid Receptors (LPA) are part of a larger family known as lysophospholipid receptor family ([http://jb.oxfordjournals.org/content/131/6/767.long EDG family]), including the archetype sphingosine-1-phosphate receptors (S1P₁). The only structure previously reported in this GPCR family was of S1P₁, and it provides a comparison for differential structure and function to LPA₁. <ref name= "Chrencik"/> A major difference was observed in ligand access between these two receptors.  The binding path in LPA₁ is located in the extracellular milieu, while in S1P₁ the ligand accesses the binding pocket through the membrane (Figure 3). The overall shape of each binding pocket is also different, as the S1P₁ binding pocket has more of an oval shape, whereas [[Image:LPA S1P.png|300px|left|thumb|'''Figure 3:''' Comparison of the binding pockets of LPA₁ and S1P₁ receptors.  The electron density (tan) of the binding pocket is shown around the ligand (purple). The limited binding sites of the receptors are shown in tan.]] the LPA₁ binding pocket has a more spherical shape (Figure 3).  This is due to a change in three of the amino acids present for each receptor.  At position 129 LPA₁ has an aspartate and S1P₁.  LPA₁ has a tryptophan while S1P₁ has a cysteine at position 210.  The third change occurs at position 274 for LPA₁ is a glycine and S1P₁ has a leucine <ref name= "Chrencik"/>.  The more spherical binding pocket for LPA₁ gives it the ability to recognize a larger group of chemical species.  In particular, LPA₁ has the ability to bind with ligands that have acyl chains of varying lengths <ref name= "Chrencik"/>.  Since LPA₁ binds with a variety of acyl chains, it can be used in multiple pathways.