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Structural prerequisites for G-protein activation by the neurotensin receptor

Author

Listed:
  • Brian E. Krumm

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

  • Jim F. White

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

  • Priyanka Shah

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

  • Reinhard Grisshammer

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

Abstract

We previously determined the structure of neurotensin receptor NTSR1 in an active-like conformation with six thermostabilizing mutations bound to the peptide agonist neurotensin. This receptor was unable to activate G proteins, indicating that the mutations restricted NTSR1 to relate agonist binding to G-protein activation. Here we analyse the effect of three of those mutations (E166A3.49, L310A6.37, F358A7.42) and present two structures of NTSR1 able to catalyse nucleotide exchange at Gα. The presence of F3587.42 causes the conserved W3216.48 to adopt a side chain orientation parallel to the lipid bilayer sealing the collapsed Na+ ion pocket and linking the agonist with residues in the lower receptor part implicated in GPCR activation. In the intracellular receptor half, the bulkier L3106.37 side chain dictates the position of R1673.50 of the highly conserved D/ERY motif. These residues, together with the presence of E1663.49 provide determinants for G-protein activation by NTSR1.

Suggested Citation

  • Brian E. Krumm & Jim F. White & Priyanka Shah & Reinhard Grisshammer, 2015. "Structural prerequisites for G-protein activation by the neurotensin receptor," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8895
    DOI: 10.1038/ncomms8895
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    Cited by:

    1. Christoph Klenk & Maria Scrivens & Anina Niederer & Shuying Shi & Loretta Mueller & Elaine Gersz & Maurice Zauderer & Ernest S. Smith & Ralf Strohner & Andreas Plückthun, 2023. "A Vaccinia-based system for directed evolution of GPCRs in mammalian cells," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Kazem Asadollahi & Sunnia Rajput & Lazarus Andrew Zhang & Ching-Seng Ang & Shuai Nie & Nicholas A. Williamson & Michael D. W. Griffin & Ross A. D. Bathgate & Daniel J. Scott & Thomas R. Weikl & Guy N., 2023. "Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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