Journal
NATURE
Volume 490, Issue 7421, Pages 508-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11558
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Funding
- National Institutes of Health (National Institute of Neurological Disorders and Stroke)
- National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases)
- Pfizer Global Research and Development
- MRCT Development Gap Fund
- UK Medical Research Council [MRC U105197215]
- National Institutes of Health [U54GM075026]
- NIH Roadmap grant [P50 GM073197]
- US Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]
- MRC [MC_U105197215] Funding Source: UKRI
- Medical Research Council [MC_U105197215] Funding Source: researchfish
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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 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.
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