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, Reinhard Grisshammer

Research output: Contribution to journalArticle

332 Scopus citations

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 2.8Å 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.

Original languageEnglish (US)
Pages (from-to)508-513
Number of pages6
JournalNature
Volume490
Issue number7421
DOIs
StatePublished - Oct 25 2012

ASJC Scopus subject areas

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    White, J. F., Noinaj, N., Shibata, Y., Love, J., Kloss, B., Xu, F., Gvozdenovic-Jeremic, J., Shah, P., Shiloach, J., Tate, C. G., & Grisshammer, R. (2012). Structure of the agonist-bound neurotensin receptor. Nature, 490(7421), 508-513. https://doi.org/10.1038/nature11558