Receptor: Difference between revisions

LPA₁ lies in the membrane 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). The intracellular region of this membrane protein is coupled to a heterotrimeric G protein. Three native <scene name='72/721545/Disulfides/5'>disulfide bonds</scene> in the extracellular region of this receptor provide fold stability. The 1st disulfide bond constrains the N terminal helix to extracellular loop (ECL) 2. The 2nd disulfide bond shapes ECL2, and the 3rd binds ECL3 to one of the TM α-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 6 turn α-helix and 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. The biological ligand of the LPA₁ receptor receptor is lysophosphatidic acid (LPA), a phospholipid that contains a long, nonpolar tail, a phosphate head, a chiral hydroxyl group, and an ester group. This receptor provides specificity for its ligand by the amphipathic binding pocket; the positive region on the left hand side of the pocket stabilizes the LPA's phosphate group, the nonpolar region at the bottom of the binding pocket stabilizes the hydrophobic tail of LPA, and the polar region at the top of the pocket stabilize binding of the ester and hydroxyl group. The <scene name='72/721545/Ligand/4'>binding pocket</scene> for LPA consists of both polar and nonpolar residues. <scene name='72/721545/All_polar_interactions/7'>Polar</scene> residues are located on the N terminus and within the binding pocket. A <scene name='72/721545/Hydrophobic_pocket/4'>hydrophobic pocket</scene> also interacts with the long acyl chain of LPA. The shape and polarity of the binding pocket makes it specific for molecules with a polar head and long hydrophobic tail shaped like LPA. ONO-9780307 (ON7) is an antagonist for LPA due to its large nonpolar region, chiral hydroxyl group, ester, and carboxylic acid which all resemble portions of the LPA molecule. 4 separate interactions with this antagonist of LPA₁ help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. In the nonpolar region of the binding pocket, <scene name='72/721543/Nonpolar/2'>three non polar residues</scene> of LPA₁ stabilize the large nonpolar group of ON7. At the polar region, the ligand binding is stabilized by <scene name='72/721543/Arg124gln125/4'>Arg124 and Glu125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. Interplay between <scene name='72/721543/Lys39_and_glu293/8'>Glu293 and Lys39</scene> causes another stabilizing component with the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all 6 LPA receptors, a neighboring His residue is specific to the LPA₁ receptor. <scene name='72/721543/His40/4'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. Protonation of this residue greatly affects the binding affinity of LPA, leading to an increase in the pathways associated with cell proliferation and migration. Because cancerous tumors create acidic environments where His40 is protonated, this residue is an important link to tumor growth and cancer cell movement.