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Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8 [Angstrom] resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS^sub 8-13^, the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity.
Neurotensin (NTS) is a short peptide that is found in the nervous system and in peripheral tissues1. NTS shows a wide range of biological activities and has important roles in Parkinson's disease and the pathogenesis of schizophrenia, the modulation of dopamine neurotransmission, hypothermia, antinociception, and in promoting the growth of cancer cells2-6. Three neurotensin receptors have been identified. NTSR1 (ref. 7) and NTSR2 (ref. 8) belong to the class A GPCR family, whereas NTSR3 (also called SORT1) is a member of the sortilin family with a single transmembrane domain9. Most of the known effects of NTS are mediated through NTSR1 (ref. 5), which signals preferentially via theGq protein.Many aspects of ligand binding to NTSR1 have been addressed by mutagenesis and modelling10-12 but the details of ligand binding remain poorly understood at the molecular level. This has limited the rational design of compounds targeting NTSR1 for therapeutic purposes5 in the absence of structural information on NTSR1 in complex with agonist or antagonist.
Recent progress in elucidating GPCR structures in complex with either small-molecule antagonists, agonists, or in complex with a heterotrimeric G protein has provided detailed molecular insights into GPCR function (reviewed in refs 13-15). However, most receptor structures are of GPCRs belonging to the a group of class A (ref. 16), which characteristically bind small endogenous agonists deep within the...