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Structure of the agonist-bound neurotensin receptor

Author

Listed:
  • 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
    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.).)

  • James Love

    (Protein Production Facility of the New York Consortium on Membrane Protein Structure, New York Structural Biology Center
    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.).)

  • 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
    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.).)

  • Jelena Gvozdenovic-Jeremic

    (Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health
    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.).)

  • 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)

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.

Suggested Citation

  • 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, 2012. "Structure of the agonist-bound neurotensin receptor," Nature, Nature, vol. 490(7421), pages 508-513, October.
    • Handle: RePEc:nat:nature:v:490:y:2012:i:7421:d:10.1038_nature11558
    DOI: 10.1038/nature11558
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    Cited by:

    1. Wenli Zhao & Wenru Zhang & Mu Wang & Minmin Lu & Shutian Chen & Tingting Tang & Gisela Schnapp & Holger Wagner & Albert Brennauer & Cuiying Yi & Xiaojing Chu & Shuo Han & Beili Wu & Qiang Zhao, 2022. "Ligand recognition and activation of neuromedin U receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Jinkang Shen & Dongqi Zhang & Yao Fu & Anqi Chen & Xiaoli Yang & Haitao Zhang, 2022. "Cryo-EM structures of human bradykinin receptor-Gq proteins complexes," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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