Structure of the agonist-bound neurotensin receptor

Jim F. White, Nicholas Noinaj, Yoko Shibata, James Love, Brian Kloss, Feng Xu, Jelena Gvozdenovic-Jeremic, Priyanka Shah, Joseph Shiloach, Christopher G. Tate and Reinhard Grisshammer ()
Additional contact information
Jim F. White: Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Nicholas Noinaj: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Yoko Shibata: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
James Love: Protein Production Facility of the New York Consortium on Membrane Protein Structure, New York Structural Biology Center
Brian Kloss: Protein Production Facility of the New York Consortium on Membrane Protein Structure, New York Structural Biology Center
Feng Xu: Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Jelena Gvozdenovic-Jeremic: Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Priyanka Shah: Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Joseph Shiloach: Biotechnology Core Lab, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Christopher G. Tate: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Reinhard Grisshammer: Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health

Nature, 2012, vol. 490, issue 7421, 508-513

Abstract: Abstract 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 NTS8–13, 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.

Date: 2012
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DOI: 10.1038/nature11558

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