Introduction
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as G protein-coupled receptors (GPCRs) and responds to the 13 amino acid hormone neurotensin (NT). There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of signal transduction across the cell membrane.[1] These receptors are involved in a vast array of physiological processes within the body that range from interactions with dopamine to effects on secretion of bile in the intestines.[2] [3] Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. (drug discovery) There are currently no NTRS1 structures of the inactive state, so there is no way to determine the conformational changes of the binding pocket caused by the binding of NT. (reference Agonist-bound)
Neurotensin
Structure
Overall Structure
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a G protein associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
Neurotensin Binding Site
Hydrophobic Stacking
A major player in the transduction of the extracellular signal to the intracellular G protein is the hydrogen bonding network that links the bound hormone with the hydrophobic core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a network between F358, W321, A157, and F317 possible.(Reference structural prereq) 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
Allosteric Effects
Sodium ions are a negative allosteric inhibitor to the binding of the neurotensin agonist to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362. This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 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. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
