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.

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Protein Data Bank

Data deposits

Coordinates and structure factors for NTSR1-GW5-T4L are deposited in the Protein Data Bank under accession code 4GRV.


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This research was supported by the Intramural Research Program of the National Institutes of Health (J.F.W., J.G.-J., P.S. and R.G.: National Institute of Neurological Disorders and Stroke; N.N. and J.S.: National Institute of Diabetes and Digestive and Kidney Diseases) and a joint grant from Pfizer Global Research and Development and the MRCT Development Gap Fund in addition to core funding from the UK Medical Research Council MRC U105197215 (Y.S., C.G.T.). The Protein Production Facility of the New York Consortium on Membrane Protein Structure was supported by the National Institutes of Health grant U54GM075026 (J.L., B.K.). We acknowledge the NIH Roadmap grant P50 GM073197 for technology development (to R. C. Stevens) for visitor support at The Scripps Research Institute. We thank the staff at the General Medicine and Cancer Institute’s Collaborative Access Team (GM/CA-CAT) beamline at the Advanced Photon Source, Argonne National Laboratory for their assistance during data collection. Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract No. DE-AC02-06CH11357.

Author information

Author notes

    • Yoko Shibata
    • , James Love
    • , Feng Xu
    •  & Jelena Gvozdenovic-Jeremic

    Present addresses: MedImmune, Milstein Building, Granta Park, Cambridge CB21 6GH, UK (Y.S.); Albert Einstein College of Medicine, Price Center, New York, New York 10461, USA (J.L.); College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China (F.X.); National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA (J.G.-J.).


  1. Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland 20852, USA

    • Jim F. White
    • , Feng Xu
    • , Jelena Gvozdenovic-Jeremic
    • , Priyanka Shah
    •  & Reinhard Grisshammer
  2. Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA

    • Nicholas Noinaj
  3. MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK

    • Yoko Shibata
    •  & Christopher G. Tate
  4. Protein Production Facility of the New York Consortium on Membrane Protein Structure, New York Structural Biology Center, New York, New York 10027, USA

    • James Love
    •  & Brian Kloss
  5. Biotechnology Core Lab, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA

    • Joseph Shiloach


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J.F.W. characterized various NTSR1 constructs by ligand binding and G protein assays, tested NTSR1 mutants for stability, and purified NTSR1 for crystallization. N.N. collected diffraction data and solved the structure. Y.S. performed alanine scanning mutagenesis and tested NTSR1 mutants for stability, and C.G.T. was responsible for the mutagenesis strategy. J.L. and B.K. explored and performed the automation of alanine scanning mutagenesis. F.X. performed crystallization experiments and stability tests. J.G.-J. and P.S. did alanine scanning and molecular biology on NTSR1. J.S. performed large-scale fermentation. R.G. performed crystallization experiments, assisted with data collection and was responsible for the overall project strategy. The manuscript was written by R.G. and C.G.T.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Reinhard Grisshammer.

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    Supplementary Information

    This file contains a Supplementary Discussion, Supplementary Abbreviations and Acknowledgements, Supplementary Tables 1-5, Supplementary Figures 1-14 and Supplementary References.

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