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

311 Citations (Scopus)

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

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Neurotensin Receptors
Neurotensin
neurotensin (8-13)
G-Protein-Coupled Receptors
Peptides
Nervous System Diseases
Analgesia
Opioid Analgesics
Neurotransmitter Agents
Obesity
Eating
Hormones
Ligands
Amino Acids
Membranes
Brain
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

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

Structure of the agonist-bound neurotensin receptor. / White, Jim F.; Noinaj, Nicholas; Shibata, Yoko; Love, James; Kloss, Brian; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Shiloach, Joseph; Tate, Christopher G.; Grisshammer, Reinhard.

In: Nature, Vol. 490, No. 7421, 25.10.2012, p. 508-513.

Research output: Contribution to journalArticle

White, JF, Noinaj, N, Shibata, Y, Love, J, Kloss, B, Xu, F, Gvozdenovic-Jeremic, J, Shah, P, Shiloach, J, Tate, CG & Grisshammer, R 2012, 'Structure of the agonist-bound neurotensin receptor', Nature, vol. 490, no. 7421, pp. 508-513. https://doi.org/10.1038/nature11558
White JF, Noinaj N, Shibata Y, Love J, Kloss B, Xu F et al. Structure of the agonist-bound neurotensin receptor. Nature. 2012 Oct 25;490(7421):508-513. https://doi.org/10.1038/nature11558
White, Jim F. ; Noinaj, Nicholas ; Shibata, Yoko ; Love, James ; Kloss, Brian ; Xu, Feng ; Gvozdenovic-Jeremic, Jelena ; Shah, Priyanka ; Shiloach, Joseph ; Tate, Christopher G. ; Grisshammer, Reinhard. / Structure of the agonist-bound neurotensin receptor. In: Nature. 2012 ; Vol. 490, No. 7421. pp. 508-513.
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