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[3] [4] [5] [6]

Introduction

Figure 1.Top view of NTSR1 protein interacting with NTS ligand

Neurotensin receptor 1 (NTSR1) is a G-protein coupled receptor (GPCR) that binds to the 13 amino acid peptide, neurotensin^[7]. Studies determining the structure of NTSR1 crystallized the GPCR bound with the C-terminus of its tridecapeptide ligand, because it has a higher potency and efficacy than its full-length counterpart^[7]. NTSR1 is a class A GPCR, and like all G-proteins, consists 7 transmembrane helices. Class A GPCRs bind their ligands within the transmembrane core, and this is seen in NTSR1. Along with the ligand binding pocket at the top of the protein, NTSR1 also contains an allosteric Na+ ion binding pocket underneath. NTS binds to NTSR1, leading to a conformational change of the protein and modulation of second messengers. NTS has been shown to have a variety of biological activities including a role in the leptin signalling pathways, tumor growth, and dopamine regulation. The majority of effects of NTS are mediated through NTSR1. Research of the structure of NTSR1 has focused on the differences between its active and active-like states.

Structure

Ligand Binding Pocket

Near the top of the protein is the This pocket is comprised of several key amino acid resides. The first reside is a Phenylalanine at position F358. The purpose of this amino acid is to take part in a network of hydrophobic stacking interactions. These interactions stabilize the Y324 and W321 residues. These are crucial interactions because the Y324 is the amino acid residue that directly interacts with the via Van der Waals interactions . Without the hydrophobic stacking interactions that are facilitated by the F358 this binding interaction would not occur. The W321 residue also partakes in these stacking interactions. The W321 serves as the boundary between the ligand binding pocket and the sodium binding pocket.

Na+ Binding Pocket

Figure 2. Residues of collapsed sodium binding pocket

, which is positioned at the bottom of the , sets the top of the . The Na+ ion binding pocket acts as a negative allosteric site for G protein activity. When Na+ enters the Na+ ion binding pocket, it coordinates with Asp95, Gln131, Ser135, and Asp113. This decreases the activity of the protein. When the G protein is in its active state, the Na+ ion binding pocket is collapsed, preventing the regulation of protein activity through a Na+ ion. In this case, the Na+ ion is unable to be coordinated by a salt bridge to Asp113. The side chain atoms of Asp113 form a hydrogen bond network with Thr156, Ser361, Ser362, and Gln365 instead, which prevents the coordination of a Na+ ion.

Neurotensin

is a 13 amino acid peptide that is found in both nervous and peripheral tissues. It functions as a hormone and a neurotransmitter by activating as the ligand for the G-protein coupled receptor NTSR1.

Biological Relevance

Leptin Research

A study was done by Liang Y. et al.to analyze the effects that being NTSR1 deficient had on mice. The results demonstrated that mice who were NTSR1 deficient were not able to receive a satiety signal.This resulted in the mice to continuing to eat as long as food was present, leading to significant weight gain. This is due to the fact that NTSR1 is involved in a signaling pathway that regulates Leptin and therefore food intake. Without sufficient NTSR1 this pathway is interrupted. ^[6]