Sandbox reserved 1169: Difference between revisions
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A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound <font color='#32CD32'>hormone</font> with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the <font color='#A9A9A9'>neurotensin receptor</font>. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Tyr324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The effects that this network has on the activation of the intracellular G-protein was examined by the [https://en.wikipedia.org/wiki/Mutagenesis mutagenesis] of amino acids involved in this network. Mutagenesis of <scene name='72/727765/Overall_structure/12'>A86L</scene>, <scene name='72/727765/Overall_structure/13'>E166A</scene>, <scene name='72/727765/Overall_structure/14'>G125L</scene>, <scene name='72/727765/Overall_structure/15'>L310A</scene>, <scene name='72/727765/Overall_structure/16'>F358A</scene>, and <scene name='72/727765/Overall_structure/17'>V360A</scene> showed that when this interaction was disrupted, the receptor no longer was able to activate the G-protein. <ref name="Krumm"/> This discovery lead to the conclusion that the conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G-protein. | A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound <font color='#32CD32'>hormone</font> with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the <font color='#A9A9A9'>neurotensin receptor</font>. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Tyr324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The effects that this network has on the activation of the intracellular G-protein was examined by the [https://en.wikipedia.org/wiki/Mutagenesis mutagenesis] of amino acids involved in this network. Mutagenesis of <scene name='72/727765/Overall_structure/12'>A86L</scene>, <scene name='72/727765/Overall_structure/13'>E166A</scene>, <scene name='72/727765/Overall_structure/14'>G125L</scene>, <scene name='72/727765/Overall_structure/15'>L310A</scene>, <scene name='72/727765/Overall_structure/16'>F358A</scene>, and <scene name='72/727765/Overall_structure/17'>V360A</scene> showed that when this interaction was disrupted, the receptor no longer was able to activate the G-protein. <ref name="Krumm"/> This discovery lead to the conclusion that the conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G-protein. | ||
== Sodium Binding Pocket == | == Sodium Binding Pocket == | ||
Conserved across all class A GPCRs, a <scene name='72/727765/Sodium_binding_pocket_final/1'>sodium binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The sodium ion is coordinated with a highly conserved Asp113 and four other oxygen contacts from a combination of water molecules. For G-protein activation to occur, a | Conserved across all class A GPCRs, a <scene name='72/727765/Sodium_binding_pocket_final/1'>sodium binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The sodium ion is coordinated with a highly conserved Asp113 and four other oxygen contacts from a combination of water molecules. For G-protein activation to occur, a hydrogen bond coordination with T156, S362, and N365 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif] must occur. The binding of Na<sup>+</sup> within this site disrupts the coordination of the hydrogen bonds and places the receptor in its inactive form. <ref name="Katritch">PMID:24767681</ref> | ||
=== Allosteric Effects === | === Allosteric Effects === | ||
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. Sodium's binding causes for the receptor to favor its inactive state. Asp113 of the highly conserved D/RY motif and Asn365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and filling the sodium binding pocket. Trp321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. Trp321 uses van der Walls interactions to place it in the conformation necessary to block sodium from entering the site. By not allowing for sodium to enter this binding site, the receptor is able to conform to its active state and activate the G-protein that is associated with it. | Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. Sodium's binding causes for the receptor to favor its inactive state. Asp113 of the highly conserved D/RY motif and Asn365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and filling the sodium binding pocket. Trp321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. Trp321 uses van der Walls interactions to place it in the conformation necessary to block sodium from entering the site. By not allowing for sodium to enter this binding site, the receptor is able to conform to its active state and activate the G-protein that is associated with it. | ||
