Structural prerequisites for G-protein activation by the neurotensin receptor

Brian E. Krumm, Jim F. White, Priyanka Shah and Reinhard Grisshammer ()
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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

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8895

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