Journal Article

Structure of the agonist-bound neurotensin receptor

Shiloach, Joseph, Love, James, Gvozdenovic-Jeremic, Jelena, Xu, Feng, White, Jim F., Shah, Priyanka, Shibata, Yoko, Grisshammer, Reinhard, Kloss, Brian, Noinaj, Nicholas, Tate, Christopher G.

2012

Overview

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 Å resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS 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. The X-ray crystal structure of a rat neurotensin receptor in complex with the C-terminal portion of neurotensin is presented; this is the first structure of a member of the β group of class A G-protein-coupled receptors. GPCR–peptide agonist structure determined Neurotensin is a short peptide that can act as a neurotransmitter, a digestive hormone, and a regulator of cardiac output and blood pressure. In this manuscript, the authors solve an X-ray crystal structure of the carboxy-terminal portion of neurotensin bound to a rat neurotensin receptor. This is the first structure of a member of the beta group of class A G-protein-coupled receptors (GPCRs), and the first published structure of a GPCR bound to a peptide agonist. This structure should facilitate the development of non-peptide drugs that could be used to treat neurological disorders, cancer and obesity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378 / 631/45/535 / 631/45/612/194 / Agonists (Biochemistry) / Amino Acid Motifs / Amino Acid Sequence / Analysis / Analytical, structural and metabolic biochemistry / Animals / Bacteriophage T4 / Binding Sites / Biochemistry / Biological and medical sciences / Cell receptors / Cell structures and functions / Chemokines / Crystal structure / Crystallization / Crystallography, X-Ray / Enzymes / Fundamental and applied biological sciences. Psychology / Health aspects / Hormone receptors / Humanities and Social Sciences / Hydrogen bonds / Ligands / Miscellaneous / Models, Molecular / Molecular and cellular biology / multidisciplinary / Muramidase / Mutagenesis / Mutation / Neurotensin / Neurotensin - chemistry / Neurotensin - genetics / Neurotensin - metabolism / Physiological aspects / Protein Conformation / Proteins / Rats / Receptors, Neurotensin - agonists / Receptors, Neurotensin - chemistry / Receptors, Neurotensin - genetics / Receptors, Neurotensin - metabolism / Science / Structure