2016-03-30T03:12:15Z

Brent Waibel:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]' scene='72/721539/Overall_structure/3'/>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> 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. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/1'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
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 <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> 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 [https://en.wikipedia.org/wiki/G_protein 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 ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe 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 <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> 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 ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/3'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== 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. 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.<ref name="Krumm"/> 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.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

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== References ==
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