Sandbox Reserved 1172: Difference between revisions
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=== Key Ligand Interactions === | === Key Ligand Interactions === | ||
[[Image:Pic2proteo3.png|200 px|right|thumb|Figure 2: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.The exterior of the protein was partially cut away to display the interior binding pocket.]] | [[Image:Pic2proteo3.png|200 px|right|thumb|Figure 2: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.The exterior of the protein was partially cut away to display the interior binding pocket.]] | ||
The biological ligand of the LPA<sub>1</sub> receptor receptor is [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a phospholipid that contains a long, nonpolar tail, a phosphate head, a chiral hydroxyl group, and an ester group. [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8589 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. | The biological ligand of the LPA<sub>1</sub> receptor receptor is [https://en.wikipedia.org/wiki/Lysophosphatidic_acid 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 lefthand 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 (Figure 1). [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8589 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. Three separate interactions with antagonist of LPA<sub>1</sub>, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the ligand binding is stabilized by <scene name='72/721543/Arg124gln125/3'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/7'>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.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a neighboring histidine residue is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue to greatly affects the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref> | ||
